Diazonamide analogs

ABSTRACT

Novel diazonamide analogs having anti-mitotic activity, useful for the treatment of cancer and other proliferative disorders are provided.

RELATED APPLICATIONS

This application is a continuation of Ser. No. 12/471,246 filed May 22,2009 (now, U.S. Pat. No. 8,153,619), which claims benefit of priority toU.S. Provisional Application Ser. No. 61/055,400, filed 22 May 2008; andU.S. Provisional Application Ser. No. 61/084,152, filed 28 Jul. 2008;U.S. Provisional Application Ser. No. 61/112,069, filed 6 Nov. 2008; andU.S. Provisional Application Ser. No. 61/114,376, filed 13 Nov. 2008.The contents of these documents are incorporated herein by reference intheir entirety.

TECHNICAL FIELD

The invention relates to diazonamide analogs having anti-mitoticactivity, and to salts, pharmaceutical compositions, and conjugatesthereof, which are useful as anti-proliferative agents.

BACKGROUND ART

Diazonamide A is a mitotic spindle-disrupting agent first isolated fromthe marine organism Diazona angulata, having the structure:

The preparation of diazonamide analogs via macrocyclic indolineintermediates bearing a carbobenzyloxy (Cbz) or o-nitrophenylsulfonylprotected amino group has been previously described. U.S. Pat. No.7,022,720 correctly discloses the structure of diazonamide A anddescribes the synthesis of some of its analogs. U.S. application Ser.No. 11/264,502, a continuation-in-part of U.S. application Ser. No.10/227,509 (now U.S. Pat. No. 7,022,720) was filed 31 Oct. 2005, and ispublished as US 2006/0089397. U.S. Ser. No. 11/591,016, acontinuation-in-part of U.S. application Ser. No. 11/264,502, was filed31 Oct. 2006, and is published as US 2007/0149583. U.S. application Ser.No. 12/134,984, filed 6 Jun. 2008, and published as US 2009/0005572,describes synthetic methods for the preparation of diazonamide analogsvia indoline intermediates.

DISCLOSURE OF THE INVENTION

The present invention is directed towards compounds of formula (I)

and the pharmaceutically acceptable salts and conjugates thereof. Theinvention is also directed towards pharmaceutical compositionscomprising a compound of formula (I) and/or a salt thereof, to modifiedforms of such compounds conjugated to stabilizing or targeting agents,and to methods of treating proliferative diseases, in particularcancers, using these compounds and formulations.

In one aspect, the invention provides a compound of formula (I):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹ is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C6aryl, C6-C12 arylalkyl, or a heteroform of one of these, each of whichmay be optionally substituted;

R² is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14heteroarylalkyl, each of which may be optionally substituted; or

R¹ and R² may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered azacyclicring, optionally containing an additional heteroatom selected from N, O,and S as a ring member;

R⁴ is H, or C1-C4 alkyl;

R⁵ is H, or C1-C8 alkyl, C2-C12 alkenyl, C3-C8 cycloalkyl, C4-C12cycloalkylalkyl, C2-C12 alkynyl, C6-C12 aryl, C6-C14 arylalkyl,alkylsulfonyl, or arylsulfonyl, or a heteroform of one of these, each ofwhich may be optionally substituted; or is —C(═O)R³ where R³ is C1-C12alkyl, C1-C12 heteroalkyl, C2-C12 alkenyl, C2-C12 heteroalkenyl, C3-C8cycloalkyl, C3-C8 heterocyclyl, C4-C12 cycloalkylalkyl, C4-C12heterocyclylalkyl, C6-C12 aryl, C5-C12 heteroaryl, C6-C14 arylalkyl, orC6-C14 heteroarylalkyl, each of which may be optionally substituted; oris —C(═O)OR¹² or —C(═S)OR¹², where R¹² is C1-C8 alkyl, C2-C8 alkenyl, orC2-C8 alkynyl; or

R⁴ and R⁵ may be taken together with nitrogen to form an optionallysubstituted 3- to 8-membered azacyclic ring, optionally containing anadditional heteroatom selected from N, O, and S as a ring member;

R⁶ and R⁷ are independently H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14arylalkyl, C6-C14 heteroarylalkyl, C1-C6 acyl, C6-C12 aroyl,alkylsulfonyl, or arylsulfonyl, each of which may be optionallysubstituted;

R⁸ and R⁹ are independently H, halo, or C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C6-C12 aryl, C5-C12 heteroaryl, each of which may beoptionally substituted, or COOR¹¹ or CONR¹¹ ₂, where each R¹¹ isindependently H or C1-C4 alkyl;

m, m′ and m″ are independently 0-3; and

each Y, Y′ and Y″ is independently halo, OH, C1-C4 alkoxy, or C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl,or a heteroform of one of these, each of which may be optionallysubstituted.

In another aspect, the invention provides a compound of formula (I-A):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹ is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C6aryl, C6-C12 arylalkyl, or a heteroform of one of these, each of whichmay be optionally substituted;

R² is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14heteroarylalkyl, each of which may be optionally substituted; or

R¹ and R² may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered azacyclicring, optionally containing an additional heteroatom selected from N, O,and S as a ring member;

R⁴ is H, or C1-C4 alkyl;

R⁵ is H, or C1-C8 alkyl, C2-C12 alkenyl, C3-C8 cycloalkyl, C4-C12cycloalkylalkyl, C2-C12 alkynyl, C6-C12 aryl, C6-C14 arylalkyl,alkylsulfonyl, or arylsulfonyl, or a heteroform of one of these, each ofwhich may be optionally substituted; or is —C(═O)R³ where R³ is C1-C12alkyl, C1-C12 heteroalkyl, C2-C12 alkenyl, C2-C12 heteroalkenyl, C3-C8cycloalkyl, C3-C8 heterocyclyl, C4-C12 cycloalkylalkyl, C4-C12heterocyclylalkyl, C6-C12 aryl, C5-C12 heteroaryl, C6-C14 arylalkyl, orC6-C14 heteroarylalkyl, each of which may be optionally substituted; or

R⁴ and R⁵ may be taken together with nitrogen to form an optionallysubstituted 3- to 8-membered azacyclic ring, optionally containing anadditional heteroatom selected from N, O, and S as a ring member;

R⁶ and R⁷ are independently H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14arylalkyl, C6-C14 heteroarylalkyl, C1-C6 acyl, C6-C12 aroyl,alkylsulfonyl, or arylsulfonyl, each of which may be optionallysubstituted;

R⁸ and R⁹ are independently H, halo, or C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C6-C12 aryl, or C5-C12 heteroaryl, each of which may beoptionally substituted;

m, m′ and m″ are independently 0-3; and

each Y, Y′ and Y″ is independently halo, OH, C1-C4 alkoxy, or C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl,or a heteroform of one of these, each of which may be optionallysubstituted.

In another aspect, the invention provides a compound of formula (II):

or a pharmaceutically acceptable salt or conjugate thereof,

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y, Y″, m and m″ are defined as forformula (I).

In further aspect, the invention provides a compound of formula (III):

or a pharmaceutically acceptable salt or conjugate thereof,

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y, Y″, m and m″ are defined as forformula (I).

In another aspect, the invention provides a compound of formula (IV):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein X is O, S, NR″ or (CH₂)_(n), where n is 0-2, and R″ is H, C1-C8alkyl, C5-C8 aryl, C6-C12 arylalkyl, C1-C6 acyl, C6-C12 aroyl,alkylsulfonyl, or arylsulfonyl; and

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Y, Y′, Y″, m, m′ and m″ are defined as forformula (I).

In another aspect, the invention provides a compound of formula (V):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹, R², R⁸, R⁹, Y, Y″, m and m″ are defined as for formula (I);

Z is OH, OR, CH₂OR, SR, or NR₂, where each R is independently H,optionally fluorinated C1-C4 alkyl, or optionally fluorinated C1-C4acyl; and

each of R^(10a) and R^(10b) is independently C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12 aryl,C6-C20 arylalkyl, or a heteroform of one of these, each of which may beoptionally substituted; or

R^(10a) and R^(10b) may be taken together with the carbon to which theyare attached to form a C3-C8 cycloalkyl or a C3-C8 heterocyclyl ring,which may be optionally substituted.

In a further aspect, In another aspect, the invention provides acompound of formula (VI):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹, R², R⁸, R⁹, Y, Y″, m and m″ are defined as for formula (I);

Z is OH, OR, CH₂OR, SR, or NR₂, where each R is independently H,optionally fluorinated C1-C4 alkyl, or optionally fluorinated C1-C4acyl; and

R¹⁰ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl,C3-C8 cycloalkylalkyl, C6-C12 aryl, C6-C20 arylalkyl, or a heteroform ofone of these, each of which may be optionally substituted.

The invention also provides a pharmaceutical composition comprising atleast one compound of any of the formulae or any of the embodimentsshown herein, and a pharmaceutically acceptable excipient.Pharmaceutical compositions may also comprise pharmaceuticallyacceptable salts or conjugated forms of the compounds of the inventiondescribed herein.

In another aspect, the invention provides a method for treating orameliorating a cell proliferative disorder, comprising administering toa subject in need thereof a therapeutically effective amount of at leastone compound of formulae (I), (II), (III), (IV), (V) or (VI) or a salt,conjugate, or pharmaceutical composition thereof. In some embodiments,the amount administered is sufficient to inhibit cell proliferation. Inother embodiments, the amount is sufficient to slow tumor growth orreduce tumor size. In some embodiments, the compound of formulae(I)-(VI) is used in combination with another chemotherapeutic agent orapproach.

Provided also are methods for inhibiting cell proliferation, comprisingcontacting cells with a compound as described herein, or a salt, orconjugate thereof, in an amount effective to inhibit cell proliferation.In some embodiments, the cells are in a cell line, such as a cancer cellline (e.g., a cell line derived from breast, prostate, colon, rectal,melanoma, pancreatic, lung, or hematopoietic cancers, etc.). The cellssometimes are in a tissue, and sometimes are in a tumor in a subject. Inother embodiments, the cells are in a tumor, and sometimes are in atumor in a subject. In certain embodiments, the method further comprisesinducing cell apoptosis.

Provided also are methods for treating cancer in a subject in need ofsuch treatment, comprising: administering to the subject atherapeutically effective amount of a compound of any one of formulae(I)-(VI) or a salt or conjugate thereof, as further described herein, inan amount that is effective to treat or ameliorate said cancer.

In some embodiments, the compound of formula (I)-(VI) is a compound inone of the Tables provided herein, or a pharmaceutically acceptable saltor conjugate of one of these compounds.

The invention further provides methods for treating or ameliorating acondition related to aberrant cell proliferation. For example, providedare methods of treating or ameliorating a cell proliferative disorder ina subject, comprising administering a compound of any one of formulae(I)-(VI) or a salt or conjugate thereof, as described herein, to asubject in need thereof in an amount effective to treat or amelioratethe condition.

In the methods described herein, the subject may be a research animal(e.g., rodent, dog, cat, monkey), optionally containing a tumor such asa xenograft tumor (e.g., human tumor), for example, or may be a human.

These and other embodiments of the invention are described in thedescription that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the inhibition of tumor growth in a mouse MiaPaca(pancreatic cancer) xenograft model for animals treated with Compound J(Ex. 16), and the compounds of Example 24, Example 23 and Example 53 at20 mg/kg.

FIG. 2 shows the inhibition of tumor growth in a mouse MDA-MB-231N1(breast cancer) xenograft model for animals treated with Compound J (Ex.16), and the compound of Example 24 at 20 mg/kg.

FIG. 3 shows the inhibition of tumor growth in a mouse Colo205 (coloncancer) xenograft model for animals treated with the compound of Example24 at 20 mg/kg.

FIG. 4 shows the inhibition of tumor growth in a mouse MDA-MB231N1(breast cancer) xenograft model for animals treated with the compound ofExample 24 at doses of 40 mg/kg, 20 mg/kg and 10 mg/kg.

FIG. 5 shows the inhibition of tumor growth in a mouse MDA-MBA435(breast cancer) xenograft model for animals treated with the compound ofExample 24 at 20 mg/kg.

FIG. 6 shows the inhibition of tumor growth in a mouse MiaPaca(pancreatic cancer) xenograft model for animals treated with thecompound of Example 24 at 20 mg/kg and 10 mg/kg.

FIG. 7 shows the inhibition of tumor growth in a mouse HT29 (coloncancer) xenograft model for animals treated with the compound of Example24 Example at 40 mg/kg.

FIG. 8 shows the inhibition of tumor growth in a mouse HPAC (pancreaticcancer) xenograft model for animals treated with the compound of Example24 at 20 mg/kg.

FIG. 9 shows the inhibition of tumor growth in a mouse A2058 (melanoma)xenograft model for animals treated with the compound of Example 24 at40 mg/kg and 20 mg/kg.

FIG. 10 summarizes the in vivo data for the compound of Example 24.

MODES OF CARRYING OUT THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of the preferred embodiments of theinvention and the Examples included herein. It is to be understood thatthe terminology used herein is for the purpose of describing specificembodiments only and is not intended to be limiting. It is further to beunderstood that unless specifically defined herein, the terminology usedherein is to be given its traditional meaning as known in the relevantart.

As used herein, the singular forms “a”, “an”, and “the” include pluralreferences unless indicated otherwise.

As used herein, the term “subject” refers to a human or animal subject.In preferred embodiments, the subject is human.

The terms “treat”, “treating” or “treatment” in reference to aparticular disease or disorder include prevention of the disease ordisorder, and/or lessening, improving, ameliorating, alleviating orremoving the symptoms and/or pathology of the disease or disorder.

The term “therapeutically effective amount” or “effective amount” isintended to mean that amount of a drug or pharmaceutical agent that willelicit a biological or medical response of a cell, tissue, system,animal or human that is being sought by a researcher, veterinarian,medical doctor or other clinician. The terms also can refer to reducingor stopping a cell proliferation rate (e.g., slowing or halting tumorgrowth) or reducing the number of proliferating cancer cells (e.g.,removing part or all of a tumor). Sometimes, the rate or cellproliferation is reduced by 10%, 20%, 30%, 40%, 50%, 60%, or 70% ormore. Sometimes, the number of proliferating cells is reduced by 10%,20%, 30%, 40%, 50%, 60%, or 70% or more.

As used herein, the terms “alkyl,” “alkenyl” and “alkynyl” includestraight-chain, branched-chain and cyclic monovalent hydrocarbylradicals, and combinations of these, which contain only C and H whenthey are unsubstituted. Examples include methyl, ethyl, isopropyl,isobutyl, tert-butyl, cyclohexyl, cyclopentylethyl, 2-propenyl,3-butynyl, and the like. The total number of carbon atoms in each suchgroup is sometimes described herein, e.g., when the group can contain upto twelve carbon atoms it may be described as 1-12C or as C1-C12 or asC1-12 or as C₁₋₁₂. When heteroatoms (typically N, O and S) are allowedto replace carbon atoms of an alkyl, alkenyl or alkynyl group, as inheteroalkyl groups, for example, the numbers describing the group,though still written as e.g. C1-C6, represent the sum of the number ofcarbon atoms in the group plus the number of such heteroatoms that areincluded as replacements for carbon atoms in the ring or chain beingdescribed.

Typically, the alkyl, alkenyl and alkynyl substituents of the inventioncontain 1-12C (alkyl) or 2-12C (alkenyl or alkynyl). Preferably theycontain 1-8C (alkyl) or 2-10C (alkenyl or alkynyl). Sometimes theycontain 1-4C (alkyl) or 2-4C (alkenyl or alkynyl). A single group caninclude more than one type of multiple bond, or more than one multiplebond; such groups are included within the definition of the term“alkenyl” when they contain at least one carbon-carbon double bond, andthey are included within the term “alkynyl” when they contain at leastone carbon-carbon triple bond.

“Heteroalkyl”, “heteroalkenyl”, and “heteroalkynyl” and the like aredefined similarly to the corresponding hydrocarbyl (alkyl, alkenyl andalkynyl) groups, but the ‘hetero’ terms refer to groups that contain oneor more heteroatoms selected from O, S and N and combinations thereof,within the backbone residue; thus at least one carbon atom of acorresponding alkyl, alkenyl, or alkynyl group is replaced by one of thespecified heteroatoms to form a heteroalkyl, heteroalkenyl, orheteroalkynyl group. Preferably, each heteroalkyl, heteroalkenyl andheteroalkynyl group contains only 1-2 heteroatoms as part of theskeleton of backbone of the heteroalkyl group, i.e., not includingsubstituents that may be present. Exemplary heteroalkyls includealkoxyls such as O-alkyl, alkyl ethers, secondary and tertiary alkylamines, alkyl sulfides, and the like.

The typical and preferred sizes for heteroforms of alkyl, alkenyl andalkynyl groups are generally the same as for the correspondinghydrocarbyl groups, and the substituents that may be present on theheteroforms are the same as those described above for the hydrocarbylgroups. Where such groups contain N, the nitrogen atom may be present asNH or it may be substituted if the heteroalkyl or similar group isdescribed as optionally substituted. Where such groups contain S, thesulfur atom may optionally be oxidized to SO or SO₂ unless otherwiseindicated. For reasons of chemical stability, it is also understoodthat, unless otherwise specified, such groups do not include more thanthree contiguous heteroatoms as part of the heteroalkyl chain, althoughan oxo group may be present on N or S as in a nitro or sulfonyl group.Thus —C(O)NH₂ can be a C2 heteroalkyl group substituted with ═O; and—SO₂NH— can be a C2 heteroalkylene, where S replaces one carbon, Nreplaces one carbon, and S is substituted with two ═O groups.

While “alkyl” as used herein includes cycloalkyl and cycloalkylalkylgroups, the term “cycloalkyl” may be used herein to specificallydescribe a saturated or partially saturated, monocyclic or fused orspiro polycyclic, carbocycle that is connected via a ring carbon atom,and “cycloalkylalkyl” may be used to describe a carbocyclic non-aromaticgroup that is connected to the base molecule through an alkyl linker.Similarly, “heterocyclyl” may be used to describe a non-aromatic cyclicgroup that contains at least one heteroatom as a ring member and that isconnected to the molecule via a ring atom of the cyclic group, which maybe C or N; and “heterocyclylalkyl” may be used to describe such a groupthat is connected to another molecule through an alkyl linker. The sizesand substituents that are suitable for the cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl groups are the same as thosedescribed above for alkyl groups. The size of a cycloalkylalkyl orheterocyclylalkyl group describes the total number of carbon atoms or ofcarbon atoms plus heteroatoms that replace carbon atoms of an alkyl,alkenyl, alkynyl, cycloalkyl, or cycloalkylalkyl portion. As usedherein, these terms also include rings that contain a double bond ortwo, as long as the ring is not aromatic.

As used herein, “acyl” encompasses groups comprising an alkyl, alkenyl,alkynyl, aryl or arylalkyl radical attached at one of the two availablevalence positions of a carbonyl carbon atom, e.g., —C(═O)R where R is analkyl, alkenyl, alkynyl, aryl, or arylalkyl group, and heteroacyl refersto the corresponding groups wherein at least one carbon other than thecarbonyl carbon has been replaced by a heteroatom chosen from N, O andS. Thus heteroacyl includes, for example, —C(═O)OR and —C(═O)NR₂ as wellas —C(═O)-heteroaryl. Also included within the definition of heteroacylgroups are thioacyl substituents, e.g., —C(═S)R, and imine groups, e.g.,—C(═NH)R.

Acyl and heteroacyl groups are bonded to any group or molecule to whichthey are attached through the open valence of the carbonyl carbon atom.Typically, they are C1-C8 acyl groups, which include formyl, acetyl,trifluoroacetyl, pivaloyl, and benzoyl, and C2-C8 heteroacyl groups,which include methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl. Thehydrocarbyl groups, aryl groups, and heteroforms of such groups thatcomprise an acyl or heteroacyl group can be substituted with thesubstituents described herein as generally suitable substituents foreach of the corresponding component of the acyl or heteroacyl group.

“Aromatic” moiety or “aryl” moiety refers to a monocyclic or fusedbicyclic moiety having the well-known characteristics of aromaticity;examples include phenyl and naphthyl. Similarly, “heteroaromatic” and“heteroaryl” refer to such monocyclic or fused bicyclic ring systemswhich contain as ring members one or more heteroatoms selected from O, Sand N. The inclusion of a heteroatom permits aromaticity in 5-memberedrings as well as 6-membered rings. Typical heteroaromatic systemsinclude monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazinyl, thienyl, furanyl, pyrrolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,triazolyl, thiadiazolyl, oxadiazolyl, and tetrazolyl rings, and thefused bicyclic moieties formed by fusing one of these monocyclic groupswith a phenyl ring or with any of the heteroaromatic monocyclic groupsto form a C8-C10 bicyclic group such as indolyl, benzimidazolyl,indazolyl, benzotriazolyl, isoquinolinyl, quinolinyl, benzothiazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, pyrazolopyridyl,quinazolinyl, quinoxalinyl, cinnolinyl, and the like. Any monocyclic orfused ring bicyclic system which has the characteristics of aromaticityin terms of electron distribution throughout the ring system is includedin this definition. It also includes bicyclic groups where at least onering has the characteristics of aromaticity, even though it may be fusedto a nonaromatic ring. Typically, the ring systems contain 5-12 ringmember atoms. Preferably the monocyclic aryl and heteroaryl groupscontain 5-6 ring members, and the bicyclic aryl and heteroaryl groupscontain 8-10 ring members. Aryl groups sometimes contain 6-12 ringmembers and may be referred to as C6-C12 aryl; heteroaryl groupssometimes contain 5-12 ring members and may be referred to as C5-C12heteroaryl.

Similarly, “arylalkyl” and “heteroarylalkyl” refer to aromatic andheteroaromatic ring systems which are bonded to their attachment pointthrough a linking group such as an alkylene, including substituted orunsubstituted, saturated or unsaturated, cyclic or acyclic linkers.Typically the linker is C1-C8 alkyl or a hetero form thereof, preferablya C1-C4 alkyl. These linkers may also include a carbonyl group, thusmaking them able to provide substituents as an acyl or heteroacylmoieties. Sometimes, arylalkyl groups contain 7-20 carbon atoms,preferably 7-14 carbon atoms, including the aryl and alkyl portions;sometimes heteroarylalkyl groups contain 6-20 atoms, preferably 6-14atoms, including carbon atoms and heteroatoms in the alkyl andheteroaryl portions.

“Arylalkyl” groups as used herein are hydrocarbyl groups if they areunsubstituted, and are described by the total number of carbon atoms inthe ring and alkylene or similar linker Thus a benzyl group is aC7-arylalkyl group, and phenylethyl is a C8-arylalkyl. Preferably, anarylalkyl group includes one or two optionally substituted phenyl ringsand a C1-C4 alkylene that is unsubstituted or is substituted with one ortwo C1-C4 alkyl groups or C1-C4 heteroalkyl groups, where the alkyl orheteroalkyl groups can optionally cyclize to form a ring such ascyclopropane, dioxolane, or oxacyclopentane, and wherein the alkyl orheteroalkyl groups may be optionally fluorinated. Examples of arylalkylgroups include optionally substituted benzyl, phenylethyl,diphenylmethyl, and triphenylmethyl groups. Optional substituents whenpresent on the aryl ring of an arylalkyl group are the same as thosedescribed herein for an aryl ring.

“Heteroarylalkyl” as described above refers to a moiety comprising anaryl group that is attached through a linking group, and differs from“arylalkyl” in that at least one ring atom of the aryl moiety or oneatom in the linking group is a heteroatom selected from N, O and S. Theheteroarylalkyl groups are described herein according to the totalnumber of atoms in the ring and linker combined, and they include arylgroups linked through a heteroalkyl linker; heteroaryl groups linkedthrough a hydrocarbyl linker such as an alkylene; and heteroaryl groupslinked through a heteroalkyl linker. For example, heteroaryl groupsinclude pyridylmethyl, pyridylethyl, —O-benzyl, and the like.

“Alkylene” as used herein refers to a divalent hydrocarbyl group;because it is divalent, it can link two other groups together. Typicallyit refers to —(CH₂)_(n)— where n is 1-8 and preferably n is 1-4, thoughwhere specified, an alkylene can also be substituted by other groups,and can be of other lengths, and the open valences need not be atopposite ends of a chain. Thus —CH(Me)- and —C(Me)₂- may also bereferred to as alkylenes, as can a cyclic group such ascyclopropan-1,1-diyl. However, for clarity, a three-atom linker that isan alkylene group, for example, refers to a divalent group in which theavailable valences for attachment to other groups are separated by threeatoms such as —(CH₂)₃—, i.e., the specified length represents the numberof atoms linking the attachment points rather than the total number ofatoms in the hydrocarbyl group: —C(Me)₂- would thus be a one-atomlinker, since the available valences are separated by only one atom.Where an alkylene group is substituted, the substituents include thosetypically present on alkyl groups as described herein, thus —C(═O)— isan example of a one-carbon substituted alkylene. Where it is describedas unsaturated, the alkylene may contain one or more double or triplebonds.

“Heteroalkylene” as used herein is defined similarly to thecorresponding alkylene groups, but the ‘hetero’ terms refer to groupsthat contain one or more heteroatoms selected from O, S and N andcombinations thereof, within the backbone residue; thus at least onecarbon atom of a corresponding alkylene group is replaced by one of thespecified heteroatoms to form a heteroalkylene group. Thus, —C(═O)NH— isan example of a two-carbon substituted heteroalkylene, where N replacesone carbon, and C is substituted with a ═O group.

“Heteroform” as used herein refers to a derivative of a group such as analkyl, aryl, or acyl, wherein at least one carbon atom of the designatedcarbocyclic group has been replaced by a heteroatom selected from N, Oand S. Thus the heteroforms of alkyl, alkenyl, cycloalkyl, alkynyl,acyl, aryl, and arylalkyl are heteroalkyl, heteroalkenyl, heterocyclyl,heteroalkynyl, heteroacyl, heteroaryl, and heteroarylalkyl,respectively. It is understood that no more than two N, O or S atoms areordinarily connected sequentially, except where an oxo group is attachedto N or S to form a nitro or sulfonyl group, or in the case of certainheteroaromatic rings, such as triazine, triazole, tetrazole, oxadiazole,thiadiazole, and the like.

Unless otherwise indicated, the term “oxo” refers to ═O.

“Halo”, as used herein, includes fluoro, chloro, bromo and iodo. Fluoro,chloro, and bromo are often preferred.

“Amino” as used herein refers to NH₂, but where an amino is described as“substituted” or “optionally substituted”, the term includes NR₂ whereineach R is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl,or arylalkyl group or a heteroform of one of these groups, each of whichmay be optionally substituted with the substituents described herein assuitable for the corresponding type of group. The term also includesforms wherein the two R groups on one nitrogen atom are linked togetherto form a 3-8 membered monocyclic azacyclic ring or an 8-12 memberedbicyclic fused azacyclic ring system, each of which may be saturated,unsaturated or aromatic and which may contain 1-3 heteroatomsindependently selected from N, O and S as ring members, and which may beoptionally substituted with the substituents described as suitable foralkyl groups or, if NR₂ comprises an aromatic group, it may beoptionally substituted with the substituents described as typical forheteroaryl groups.

Amino groups may optionally be in a protected or unprotected form. Oneof skill in the art would appreciate that appropriate amine protectinggroups may vary depending on the functionality present in the particularmolecule and the nature of the amino group. Suitably protected aminesmay include, for example, amines protected as carbamates (e.g.,tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),fluorenylmethyloxy-carbonyl (Fmoc), allyloxycarbonyl (Alloc) or(trialkylsilyl)ethoxycarbonyl), carboxamides (e.g., formyl, acyl ortrifluoroacetyl, benzoyl), sulfonamides, phthalimides, succinimides,Schiff's base derivatives, and the like. Also included are alkyl orallyl amines, as well as trialkylsilyl protected amines.

Where an amine is present in protected form, it is sometimes desirableto remove the protecting group. Thus, the methods of the presentinvention also optionally include a step of removing any protectinggroups on an amine or aminoalkyl group.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein refer tomoieties of the form —SO₂alkyl or —SO₂aryl, where alkyl and aryl aredefined as above. Optionally fluorinated C₁₋₄alkyl, and optionallysubstituted phenyl groups are preferred for sulfonyl moieties. Thephenyl groups of an arylsulfonyl moiety may be optionally substitutedwith one or more substituents suitable for an aryl ring; for example,they may be substituted by halo, methyl, nitro, alkoxy, amino, or thelike. Such sulfonyl moieties, when present on oxygen form sulfonates.Such sulfonyl moieties form sulfonamides when present on nitrogen, andsulfones when present on carbon. Representative sulfonates include,e.g., —OSO₂Me (mesylate), —OSO₂CF₃ (triflate), —OSO₂tolyl (tosylate),and the like.

The term “alkoxycarbonyl” as used herein refers to a moiety of the form—COOR′, where R′ is C1-C8 alkyl, C2-C8 alkenyl, C5-C6 aryl, or C6-C14arylalkyl, trialkylsilyl, or the like, each of which may be optionallysubstituted. When present on nitrogen, such alkoxycarbonyl moieties formcarbamates, which are frequently used as nitrogen protecting groups. Insome such embodiments, R′ may be optionally halogenated C1-C4 alkyl(e.g., tert-butyl, methyl, ethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2,2-trichloroethyl), allyl, optionally substitutedbenzyl, fluorenylmethyl, or trialkylsilyl (e.g., triisopropylsilyl,triethylsilyl, tert-butyldimethylsilyl). When present on carbon, suchmoieties may also be referred to as carboxylate esters, carboalkoxygroups, or the like.

The term “substituted” means that the specified group or moiety bearsone or more non-hydrogen substituents. The term “unsubstituted” meansthat the specified group bears no such substituents.

“Optionally substituted” as used herein indicates that the particulargroup or groups being described may have no non-hydrogen substituents,or the group or groups may have one or more non-hydrogen substituents.If not otherwise specified, the total number of such substituents thatmay be present is equal to the number of H atoms present on theunsubstituted form of the group being described. Where an optionalsubstituent is attached via a double bond, such as a carbonyl oxygen(═O), the group takes up two available valences, so the total number ofsubstituents that may be included is reduced according to the number ofavailable valences.

Alkyl, alkenyl and alkynyl groups are often substituted to the extentthat such substitution makes sense chemically. Typical substituentsinclude, but are not limited to, halo, OH, ═O, ═N—CN, ═N—OR, ═NR, OR,NR₂, SR, SOR, SO₂R, SO₂NR₂, NRSO₂R, NRCONR₂, NRCOOR, NRCOR, CN, COOR,CONR₂, OOCR, COR, and NO₂, wherein each R is independently H, optionallyfluorinated C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8heteroalkynyl, C6-C12 aryl, C5-C12 heteroaryl, C7-C20 arylalkyl, orC6-C20 heteroarylalkyl, and each R is optionally substituted with one ormore groups selected from halo, OH, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′₂,SR′, SOR′, SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN,COOR′, CONR′₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H,optionally fluorinated C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8heteroacyl, C6-C12 aryl, C5-C12 heteroaryl, C7-C20 arylalkyl, or C6-C20heteroarylalkyl. Alkyl, alkenyl and alkynyl groups can also besubstituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C12 aryl or C5-C12heteroaryl, each of which can be substituted by the substituents thatare appropriate for the particular group. Preferred substituents whenpresent on an alkyl, alkenyl or alkynyl group, or a heteroform of one ofthese, include halo, OH, ═O, OR, SR, and NR₂, where R is defined asabove; preferably, each R is independently H, optionally fluorinatedC1-C4 alkyl, or optionally fluorinated C1-C4 acyl. Particularlypreferred substituents include OH, ═O, C1-C4 alkoxy, OAc, NHAc, NH₂, andNHMe. Sometimes, optional substituents present on an alkyl, alkenyl oralkynyl group, or a heteroform of one of these, include NRSO₂R, NRCONR₂,COOR, or CONR₂, where R is defined as above; preferably, each R isindependently H, optionally fluorinated C1-C4 alkyl, or is C6-C12 aryl,C5-C12 heteroaryl, C6-C20 arylalkyl, or C6-C20 heteroarylalkyl, each ofwhich may be optionally substituted.

Aryl and heteroaryl moieties may be substituted with a variety ofsubstituents including optionally fluorinated C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, C6-C12 aryl, C1-C8 acyl, C5-20 arylalkyl, andheteroforms of these, each of which can itself be further substituted;other substituents for aryl and heteroaryl moieties include halo, OH,OR, NR₂, SR, SOR, SO₂R, SO₂NR₂, NRSO₂R, NRCONR₂, NRCOOR, NRCOR, CN,COOR, CONR₂, OOCR, C(O)R, and NO₂, wherein each R is independently H,optionally fluorinated C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl,C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C12 aryl,C5-C12 heteroaryl, C6-C20 arylalkyl, or C6-C20 heteroarylalkyl, and eachR is optionally substituted as described above for alkyl groups. Thesubstituent groups on an aryl or heteroaryl group may of course befurther substituted with the groups described herein as suitable foreach type of group that comprises the substituent. Preferredsubstituents when present on an aryl or heteroaryl group include halo,OH, OR, SR, NR₂, CN, COOR, CONR₂, and NO₂, where R is defined as above.

Where an arylalkyl or heteroarylalkyl group is described as optionallysubstituted, the substituents may be on either the alkyl or heteroalkylportion or on the aryl or heteroaryl portion of the group. Thesubstituents optionally present on the alkyl or heteroalkyl portion arethe same as those described above for alkyl groups generally; thesubstituents optionally present on the aryl or heteroaryl portion arethe same as those described above for aryl groups generally.

In one aspect, the invention provides a compound of formula (I):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹ is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C6aryl, C6-C12 arylalkyl, or a heteroform of one of these, each of whichmay be optionally substituted;

R² is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14heteroarylalkyl, each of which may be optionally substituted; or

R¹ and R² may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered azacyclicring, optionally containing an additional heteroatom selected from N, O,and S as a ring member;

R⁴ is H, or C1-C4 alkyl;

R⁵ is H, or C1-C8 alkyl, C2-C12 alkenyl, C3-C8 cycloalkyl, C4-C12cycloalkylalkyl, C2-C12 alkynyl, C6-C12 aryl, C6-C14 arylalkyl,alkylsulfonyl, or arylsulfonyl, or a heteroform of one of these, each ofwhich may be optionally substituted; or is —C(═O)R³ where R³ is C1-C12alkyl, C1-C12 heteroalkyl, C2-C12 alkenyl, C2-C12 heteroalkenyl, C3-C8cycloalkyl, C3-C8 heterocyclyl, C4-C12 cycloalkylalkyl, C4-C12heterocyclylalkyl, C6-C12 aryl, C5-C12 heteroaryl, C6-C14 arylalkyl, orC6-C14 heteroarylalkyl, each of which may be optionally substituted; oris —C(═O)OR¹² or —C(═S)OR¹², where R¹² is C1-C8 alkyl, C2-C8 alkenyl, orC2-C8 alkynyl; or

R⁴ and R⁵ may be taken together with nitrogen to form an optionallysubstituted 3- to 8-membered azacyclic ring, optionally containing anadditional heteroatom selected from N, O, and S as a ring member;

R⁶ and R⁷ are independently H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14arylalkyl, C6-C14 heteroarylalkyl, C1-C6 acyl, C6-C12 aroyl,alkylsulfonyl, or arylsulfonyl, each of which may be optionallysubstituted;

R⁸ and R⁹ are independently H, halo, or C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C6-C12 aryl, C5-C12 heteroaryl, each of which may beoptionally substituted, or COOR¹¹ or CONR¹¹ ₂, where each R¹¹ isindependently H or C1-C4 alkyl;

m, m′ and m″ are independently 0-3; and

each Y, Y′ and Y″ is independently halo, OH, C1-C4 alkoxy, or C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl,or a heteroform of one of these, each of which may be optionallysubstituted.

In another aspect, the invention provides a compound of formula (I-A):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹ is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C6aryl, C6-C12 arylalkyl, or a heteroform of one of these, each of whichmay be optionally substituted;

R² is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14heteroarylalkyl, each of which may be optionally substituted; or

R¹ and R² may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered azacyclicring, optionally containing an additional heteroatom selected from N, O,and S as a ring member;

R⁴ is H, or C1-C4 alkyl;

R⁵ is H, or C1-C8 alkyl, C2-C12 alkenyl, C3-C8 cycloalkyl, C4-C12cycloalkylalkyl, C2-C12 alkynyl, C6-C12 aryl, C6-C14 arylalkyl,alkylsulfonyl, or arylsulfonyl, or a heteroform of one of these, each ofwhich may be optionally substituted; or is —C(═O)R³ where R³ is C1-C12alkyl, C1-C12 heteroalkyl, C2-C12 alkenyl, C2-C12 heteroalkenyl, C3-C8cycloalkyl, C3-C8 heterocyclyl, C4-C12 cycloalkylalkyl, C4-C12heterocyclylalkyl, C6-C12 aryl, C5-C12 heteroaryl, C6-C14 arylalkyl, orC6-C14 heteroarylalkyl, each of which may be optionally substituted; or

R⁴ and R⁵ may be taken together with nitrogen to form an optionallysubstituted 3- to 8-membered azacyclic ring, optionally containing anadditional heteroatom selected from N, O, and S as a ring member;

R⁶ and R⁷ are independently H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14arylalkyl, C6-C14 heteroarylalkyl, C1-C6 acyl, C6-C12 aroyl,alkylsulfonyl, or arylsulfonyl, each of which may be optionallysubstituted;

R⁸ and R⁹ are independently H, halo, or C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C6-C12 aryl, or C5-C12 heteroaryl, each of which may beoptionally substituted;

m, m′ and m″ are independently 0-3; and

each Y, Y′ and Y″ is independently halo, OH, C1-C4 alkoxy, or C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl,or a heteroform of one of these, each of which may be optionallysubstituted.

In compounds of formula (I) and (I-A), R¹ is H, or C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, C5-C6 aryl, C6-C12 arylalkyl, or a heteroform ofone of these, each of which may be optionally substituted. In certainpreferred embodiments, R¹ is optionally substituted C1-C4 alkyl, C2-C4alkenyl or C2-C4 alkynyl; in some such embodiments, R¹ is isopropyl.

In compounds of formula (I) and (I-A), R² is H, or C1-C8 alkyl, C1-C8heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, each of which maybe optionally substituted. In specific embodiments, R² is H or methyl.In certain preferred embodiments, R² is H.

In other embodiments, R¹ and R² are taken together with the atoms towhich they are attached to form an optionally substituted 5- to7-membered azacyclic ring, optionally containing an additionalheteroatom selected from N, O, and S as a ring member. In specificembodiments, R¹ and R² are taken together to form an optionallysubstituted 5- to 7-membered azacyclic ring containing no additionalheteroatoms, i.e., an optionally substituted pyrrolidine, piperidine orhomopiperidine ring. In other embodiments, R¹ and R² are taken togetherto form an optionally substituted 5- to 7-membered azacyclic ringcontaining an additional heteroatom selected from N, O and S. In somesuch embodiments, R¹ and R² are taken together to form an optionallysubstituted morpholine, thiomorpholine, piperazine, or homopiperazinering.

In compounds of formula (I) and (I-A), R⁴ is H, or C1-C4 alkyl. Inpreferred embodiments, R⁴ is H.

In certain embodiments of formula (I) and (I-A), R⁵ is H, or C1-C8alkyl, C2-C12 alkenyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C12alkynyl, C6-C12 aryl, C6-C14 arylalkyl, alkylsulfonyl, or arylsulfonyl,or a heteroform of one of these, each of which may be optionallysubstituted.

In other embodiments of formula (I) and (I-A), R⁵ is —C(═O)OR¹² or—C(═S)OR¹², where R¹² is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl.

In further embodiments of formula (I) and (I-A), R⁵ is —C(═O)R³ where R³is C1-C12 alkyl, C1-C12 heteroalkyl, C2-C12 alkenyl, C2-C12heteroalkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C4-C12cycloalkylalkyl, C4-C12 heterocyclylalkyl, C6-C12 aryl, C5-C12heteroaryl, C6-C14 arylalkyl, or C6-C14 heteroarylalkyl, each of whichmay be optionally substituted.

In certain embodiments, R⁵ is C(═O)R³, where R³ is C1-C8 alkyl, C2-C10alkenyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, or C6-C8 arylalkyl,each of which may be optionally substituted. In preferred embodiments,the alkyl group comprising part of R³ is substituted with at least onesubstituent selected from the group consisting of OH, OMe, OAc, NH₂,NHMe, CH₂OH and NHAc.

In certain embodiments of formula (I) and (I-A), R⁵ is C(═O)R³, where R³is a group of the form —C(Z)R^(10a)R^(10b), where Z is OH, OR, CH₂OR,SR, or NR₂, where each R is independently H, optionally fluorinatedC1-C4 alkyl, or optionally fluorinated C1-C4 acyl, and each of R^(10a)and R^(10b) is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12 aryl, C7-C20 arylalkyl,or a heteroform of one of these, each of which may be optionallysubstituted; or R^(10a) and R^(10b) may be taken together with thecarbon to which they are attached to form a C3-C8 cycloalkyl or a C3-C8heterocyclyl ring, which may be optionally substituted. In some suchembodiments, Z is OH, OMe, OAc, CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, orNHAc. Sometimes, Z is OH, OMe, OAc, NH₂, NHMe, or NHAc. In certainpreferred embodiments, Z is OH. In some such embodiments, each ofR^(10a) and R^(10b) is independently C1-C4 alkyl, C3-C6 cycloalkyl, oroptionally substituted phenyl. In other embodiments, the two R¹⁰ groupsmay be taken together with the carbon atom to which they are attached toform a C3-C8 cycloalkyl or a C3-C8 heterocyclyl group, each of which maybe optionally substituted.

In other embodiments of formula (I) and (I-A), R⁵ is C(═O)R³, where R³is a group of the formula —CH(Z)R¹⁰, where Z is OH, OR, CH₂OR, SR, orNR₂, where each R is independently H, optionally fluorinated C1-C4alkyl, or optionally fluorinated C1-C4 acyl, and R¹⁰ is independentlyC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8cycloalkylalkyl, C6-C12 aryl, C7-C20 arylalkyl, or a heteroform of oneof these, each of which may be optionally substituted. In some suchembodiments, Z is OH, OMe, OAc, CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, orNHAc. Sometimes, Z is OH, OMe, OAc, NH₂, NHMe, or NHAc. In certainpreferred embodiments, Z is OH.

In other embodiments of formula (I) and (I-A), R⁴ and R⁵ may be takentogether with nitrogen to form an optionally substituted 3- to8-membered azacyclic ring, optionally containing an additionalheteroatom selected from N, O, and S as a ring member.

In compounds of formula (I) and (I-A), R⁶ and R⁷ are independently H, orC1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14heteroarylalkyl, optionally fluorinated C1-C6 acyl, C6-C12 aroyl,alkylsulfonyl, or arylsulfonyl, each of which may be optionallysubstituted. In some embodiments, each of R⁶ and R⁷ is independently Hor Me. In preferred embodiments of formula (I) and (I-A), each of R⁶ andR⁷ is H. In some embodiments, a substituent at R⁶ and/or R⁷ may functionas a protecting group. It will be understood that the methods describedherein include an optional deprotection step to remove any protectinggroups present on the molecule.

In compounds of formula (I), R⁸ and R⁹ are independently H, halo, orC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C5-C12heteroaryl, each of which may be optionally substituted, or COOR¹¹ orCONR¹¹ ₂, where each R¹¹ is independently H or C1-C4 alkyl. In compoundsof formula (I-A), R⁸ and R⁹ are independently H, halo, or C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, or C5-C12 heteroaryl, each ofwhich may be optionally substituted. In certain preferred embodiments offormula (I) and (I-A), at least one of R⁸ and R⁹ is halo. In otherpreferred embodiments, R⁸ and R⁹ are both chloro. In other preferredembodiments, R⁸ and R⁹ are both H. In some embodiments of formula (I),at least one of R⁸ and R⁹ is COOR¹¹ or CONR¹¹ ₂, where each R¹¹ isindependently H or C1-C4 alkyl. In some such embodiments, R⁸ is COOR¹¹′and R¹¹ is H or methyl.

In compounds of formula (I) and (I-A), each of m, m′ and m″ is aninteger from 0-3. In certain embodiments, m is 0 or 1, and m′ and m″ are0. In other embodiments, m is 0 or 1, m′ is 0, and m″ is 1.

In compounds of formula (I) and (I-A), each Y, Y′ and Y″ isindependently is halo, OH, or C1-C4 alkoxy, or is C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl, or aheteroform of one of these, each of which may be optionally substituted.In certain preferred embodiments, m is 1; in some such embodiments, Y ishalo. In other preferred embodiments, m″ is 1; in some such embodiments,Y″ is OH or OMe.

In specific embodiments of formula (I) and (I-A), when R⁵ is —C(O)R³, R³is a C1-C8 straight chain, branched, or cycloalkyl group, each of whichis substituted on the carbon atom adjacent to the carbonyl group that ispart of R⁵ with OH, OMe, OAc, NH₂, NHMe, CH₂OH and NHAc.

The same groups described herein as useful for compounds of certainembodiments formula (I) and (I-A), are also suitable for compounds ofcertain embodiments of formulae (II), (II-A), (III), (III-A), (IV), (V),(V-A) and (VI).

In another aspect, the invention provides a compound of formula (II):

or a pharmaceutically acceptable salt or conjugate thereof,

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y, Y″, m and m″ are defined as forformula (I).

In some embodiments, the compound of formula (II) has the structure offormula (II-A) or (II-B):

or a pharmaceutically acceptable salt or conjugate thereof,

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y, Y″, m and m″ are defined as forformula (II).

It will be understood that embodiments of formula (II) described hereinalso apply to compounds of formula (II-A) and (II-B).

In compounds of formula (II), R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y, Y″, m andm″ are defined as for formula (I). In certain preferred embodiments, mis 0 or 1, and Y is halo when m is 1. In other preferred embodiments, m″is 0 or 1, and Y″ is OH or OMe when m″ is 1.

In compounds of formula (II-A), R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y and m aredefined as for formula (II). In preferred embodiments, m is 0 or 1, andY is halo when m is 1.

In compounds of formula (II-B), R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y″ and m″are defined as for formula (II). In preferred embodiments, m″ is 0 or 1,and Y″ is OH or OMe when m is 1.

In preferred embodiments of formula (II), R³ is C1-C8 alkyl, C2-C10alkenyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, or C6-C8 arylalkyl,each of which may be optionally substituted. In particularly preferredembodiments, the alkyl group comprising part of R³ is substituted withat least one substituent selected from the group consisting of OH, OMe,OAc, NH₂, NHMe, CH₂OH and NHAc.

In certain embodiments of formula (II), R³ is a group of the form—C(Z)R^(10a)R^(10b), where Z is OH, OR, CH₂OR, SR, or NR₂, where each Ris independently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl, and each of R^(10a) and R^(10b) is independentlyC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8cycloalkylalkyl, C6-C12 aryl, C7-C20 arylalkyl, or a heteroform of oneof these, each of which may be optionally substituted; or R^(10a) andR^(10b) may be taken together with the carbon to which they are attachedto form a C3-C8 cycloalkyl or a C3-C8 heterocyclyl ring, which may beoptionally substituted. In some such embodiments, Z is OH, OMe, OAc,CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc. Sometimes, Z is OH, OMe,OAc, NH₂, NHMe, or NHAc. In certain preferred embodiments, Z is OH. Insome such embodiments, each of R^(10a) and R^(10b) is independentlyC1-C4 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl. Inother embodiments, the two R¹⁰ groups may be taken together with thecarbon atom to which they are attached to form a C3-C8 cycloalkyl or aC3-C8 heterocyclyl group, each of which may be optionally substituted.

In other embodiments of formula (II), R³ is a group of the formula—CH(Z)R¹⁰, where Z is OH, OR, CH₂OR, SR, or NR₂, where each R isindependently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl, and R¹⁰ is independently C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12aryl, C7-C20 arylalkyl, or a heteroform of one of these, each of whichmay be optionally substituted. In some such embodiments, Z is OH, OMe,OAc, CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc. Sometimes, Z is OH,OMe, OAc, NH₂, NHMe, or NHAc. In certain preferred embodiments, Z is OH.In some such embodiments, R¹⁰ is C1-C4 alkyl, C3-C6 cycloalkyl, oroptionally substituted phenyl.

In some embodiments of formula (II), R⁸ and R⁹ are independently H,halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C5-C12heteroaryl, each of which may be optionally substituted, or COOR¹¹ orCONR¹¹ ₂, where each R¹¹ is independently H or C1-C4 alkyl. In someembodiments of formula (II), R⁸ and R⁹ are independently H, halo, orC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, or C5-C12heteroaryl, each of which may be optionally substituted. In frequentembodiments, each of R⁸ and R⁹ is H.

Specific embodiments described for formulae (I) and (II) are alsosuitable for compounds of formula (III), (IV), (V), and (VI).

In further aspect, the invention provides a compound of formula (III):

or a pharmaceutically acceptable salt or conjugate thereof,

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y, Y″, m and m″ are defined as forformula (I).

In some embodiments, the compound of formula (III) has the structure offormula (III-A) or (III-B):

or a pharmaceutically acceptable salt or conjugate thereof,

wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, Y and m are defined as for formula(III).

It will be understood that embodiments of formula (III) described hereinalso apply to compounds of formula (III-A) and (III-B).

In compounds of formula (III), R¹, R², R³, R⁶, R⁷, R⁸, and R⁹, Y, Y″, mand m″ are as defined for formula (I). In certain preferred embodiments,m is 0 or 1, and Y is halo when m is 1. In other preferred embodiments,m″ is 0 or 1, and Y″ is OH or OMe when m″ is 1.

In compounds of formula (III-A), R¹, R², R³, R⁶, R⁷, R⁸, and R⁹, m and Yare defined as for formula (III). In certain preferred embodiments, m is0 or 1, and Y is halo when m is 1.

In compounds of formula (III-B), R¹, R², R³, R⁶, R⁷, R⁸, and R⁹, m and Yare defined as for formula (III). In certain preferred embodiments, m″is 0 or 1, and Y″ is OH or OMe when m is 1.

In certain embodiments of formula (III), R¹ is optionally substitutedC1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; in some such embodiments,R¹ is isopropyl. In some embodiments of formula (III), R² is H ormethyl. In certain preferred embodiments, R² is H. In other embodimentsof formula (III), R¹ and R² are taken together with the atoms to whichthey are attached to form an optionally substituted 5- to 7-memberedazacyclic ring, optionally containing an additional heteroatom selectedfrom N, O, and S.

In certain embodiments of formula (III), R³ is a group of the formula—C(Z)R^(10a)R^(10b), where Z is OH, OR, CH₂OR, SR, or NR₂, where each Ris independently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl, and each of R^(10a) and R^(10b) is independentlyC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8cycloalkylalkyl, C6-C12 aryl, C7-C20 arylalkyl, or a heteroform of oneof these, each of which may be optionally substituted; or R^(10a) andR^(10b) may be taken together with the carbon to which they are attachedto form a C3-C8 cycloalkyl or a C3-C8 heterocyclyl ring, which may beoptionally substituted. In some such embodiments, Z is OH, OMe, OAc,CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc. Sometimes, Z is OH, OMe,OAc, NH₂, NHMe, or NHAc. In certain preferred embodiments, Z is OH. Insome such embodiments, each of R^(10a) and R^(10b) is independentlyC1-C4 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl. Inother embodiments, the two R¹⁰ groups may be taken together with thecarbon atom to which they are attached to form a C3-C8 cycloalkyl or aC3-C8 heterocyclyl group, each of which may be optionally substituted.

In other embodiments of formula (III), R³ is a group of the formula—CH(Z)R¹⁰, where Z is OH, OR, CH₂OR, SR, or NR₂, where each R isindependently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl, and R¹⁰ is independently C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12aryl, C7-C20 arylalkyl, or a heteroform of one of these, each of whichmay be optionally substituted. In some such embodiments, Z is OH, OMe,OAc, CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc. Sometimes, Z is OH,OMe, OAc, NH₂, NHMe, or NHAc. In certain preferred embodiments, Z is OH.

In some embodiments of formula (III), R⁸ and R⁹ are independently H,halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C5-C12heteroaryl, each of which may be optionally substituted, or COOR¹¹ orCONR¹¹ ₂, where each R¹¹ is independently H or C1-C4 alkyl. In someembodiments of formula (II), R⁸ and R⁹ are independently H, halo, orC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, or C5-C12heteroaryl, each of which may be optionally substituted. In frequentembodiments, each of R⁸ and R⁹ is H.

In specific embodiments of formula (III), the compound has the formula:

or a pharmaceutically acceptable salt or conjugate thereof,

wherein R¹, R², R³, R⁸, R⁹, Y and Y″ are defined as for formula (III).

In a preferred embodiment of formula (III), the compound has the formula(III-a) or (III-b) and each of R⁸ and R⁹ is H. In another embodiment offormula (III), the compound has the formula (III-a) or (III-b) and atleast one of R⁸ and R⁹ is chloro. In other preferred embodiments, thecompound has the formula (III-c), (III-d), (III-e) or (III-f), and Y″ isOH or OMe.

Specific embodiments described for formulae (I), (II), and (III) arealso suitable for compounds of formula (IV), (V), and (VI).

In another aspect, the invention provides a compound of formula (IV):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein X is O, S, NR″ or (CH₂)_(n), where n is 0-2, and R″ is H, C1-C8alkyl, C5-C8 aryl, C6-C12 arylalkyl, C1-C6 acyl, C6-C12 aroyl,alkylsulfonyl, or arylsulfonyl; and

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Y, Y′, Y″, m, m′ and m″ are defined as forformula (I).

In certain embodiments of formula (IV), the compound has the formula of(IV-A) or (IV-B):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R³, R⁸, R⁹, Y, Y″, m, m″ and X are defined as for formula (IV).

It will be understood that embodiments of formula (IV) described hereinalso apply to compounds of formula (IV-A) and (IV-B).

In compounds of formula (IV), R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Y, Y′, Y″, m, m′and m″ are defined as for formula (I). In compounds of formula (IV), Xis O, S, NR″ or (CH₂)_(n), where n is 0-2, and R″ is H, C1-C8 alkyl,C5-C8 aryl, C6-C12 arylalkyl, C1-C6 acyl, C6-C12 aroyl, alkylsulfonyl,or arylsulfonyl. In certain preferred embodiments, X is (CH₂)_(n), wheren is 0-2.

In compounds of formula (IV), R⁴ is H, or C1-C4 alkyl. In preferredembodiments, R⁴ is H. In some embodiments of formula (IV), R⁵ is—C(═O)R³ where R³ is C1-C12 alkyl, C1-C12 heteroalkyl, C2-C12 alkenyl,C2-C12 heteroalkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C4-C12cycloalkylalkyl, C4-C12 heterocyclylalkyl, C6-C12 aryl, C5-C12heteroaryl, C6-C14 arylalkyl, or C6-C14 heteroarylalkyl, each of whichmay be optionally substituted. In certain embodiments, R⁵ is C(═O)R³,where R³ is C1-C8 alkyl, C2-C10 alkenyl, C3-C6 cycloalkyl, C4-C8cycloalkylalkyl, or C6-C8 arylalkyl, each of which may be optionallysubstituted. In preferred embodiments, the alkyl group comprising partof R³ is substituted with at least one substituent selected from thegroup consisting of OH, OMe, OAc, NH₂, NHMe, CH₂OH and NHAc.

In some embodiments of formula (IV) where R⁵ is C(═O)R³, or in someembodiments of formula (IV-A) or (IV-B), R³ is a group of the form—C(Z)R^(10a)R^(10b), where Z is OH, OR, CH₂OR, SR, or NR₂, where each Ris independently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl. In such embodiments, each of R^(10a) and R^(10b)is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12 aryl, C7-C20 arylalkyl, or aheteroform of one of these, each of which may be optionally substituted;or R^(10a) and R^(10b) may be taken together with the carbon to whichthey are attached to form a C3-C8 cycloalkyl or a C3-C8 heterocyclylring, which may be optionally substituted. In some such embodiments, Zis OH, OMe, OAc, CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc.Sometimes, Z is OH, OMe, OAc, NH₂, NHMe, or NHAc. In certain preferredembodiments, Z is OH.

In other embodiments of formula (IV) where R⁵ is C(═O)R³, or in someembodiments of formula (IV-A) or (IV-B), R³ is a group of the formula—CH(Z)R¹⁰, where Z is OH, OR, CH₂OR, SR, or NR₂, where each R isindependently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl, and R¹⁰ is independently C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12aryl, C7-C20 arylalkyl, or a heteroform of one of these, each of whichmay be optionally substituted. In some such embodiments, Z is OH, OMe,OAc, CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc. Sometimes, Z is OH,OMe, OAc, NH₂, NHMe, or NHAc. In certain preferred embodiments, Z is OH.

In some embodiments of formula (IV), (IV-A) and (IV-B), R⁸ and R⁹ areindependently H, halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,C6-C12 aryl, C5-C12 heteroaryl, each of which may be optionallysubstituted, or COOR¹¹ or CONR¹¹ ₂, where each R¹¹ is independently H orC1-C4 alkyl. In other embodiments of formula (IV), (IV-A) and (IV-B), R⁸and R⁹ are independently H, halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C6-C12 aryl, C5-C12 heteroaryl, each of which may be optionallysubstituted. In frequent embodiments, each of R⁸ and R⁹ is H.

Specific embodiments described for formulae (I), (II), (III), and (IV)are also suitable for compounds of formula (V) or (VI).

In a preferred aspect, the invention provides a compound of formula (V):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R′, R², R⁸, R⁹, Y, Y″, m and m″ are defined as for formula (I);

Z is OH, OR, CH₂OR, SR, or NR₂, where each R is independently H,optionally fluorinated C1-C4 alkyl, or optionally fluorinated C1-C4acyl; and

each of R^(10a) and R^(10b) is independently C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12 aryl,C6-C20 arylalkyl, or a heteroform of one of these, each of which may beoptionally substituted; or

R^(10a) and R^(10b) may be taken together with the carbon to which theyare attached to form a C3-C8 cycloalkyl or a C3-C8 heterocyclyl ring,which may be optionally substituted.

In some embodiments, the compound of formula (V) has the structure offormula (V-A) or (V-B):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹, R², R⁸, R⁹, Y, Y″, m, m″, Z, R^(10a) and R^(10b) are definedas for formula (V).

It will be understood that embodiments of formula (V) described hereinalso apply to compounds of formula (V-A) and (V-B).

In certain embodiments of Formula (V), R¹ is optionally substitutedC1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; in some such embodiments,R¹ is isopropyl. In some embodiments of formula (V), R² is H or C1-C4alkyl; sometimes, R² is H or methyl. In certain preferred embodiments,R² is H. In other embodiments, R¹ and R² are taken together with theatoms to which they are attached to form an optionally substituted 5- to7-membered azacyclic ring, optionally containing an additionalheteroatom selected from N, O, and S as a ring member. In specificembodiments, R¹ and R² are taken together to form an optionallysubstituted 5- to 7-membered azacyclic ring containing no additionalheteroatoms, i.e., an optionally substituted pyrrolidine, piperidine orhomopiperidine ring. In other embodiments, R¹ and R² are taken togetherto form an optionally substituted 5- to 7-membered azacyclic ringcontaining an additional heteroatom selected from N, O and S. In somesuch embodiments, R¹ and R² are taken together to form an optionallysubstituted morpholine, thiomorpholine, piperazine, or homopiperazinering.

In some embodiments of formula (V), R⁸ and R⁹ are independently H, halo,or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C5-C12heteroaryl, each of which may be optionally substituted, or COOR¹¹ orCONR¹¹ ₂, where each R¹¹ is independently H or C1-C4 alkyl. In otherembodiments of formula (V), (V-A) and (V-B), R⁸ and R⁹ are independentlyH, halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, orC5-C12 heteroaryl, each of which may be optionally substituted. Incertain embodiments, at least one of R⁸ and R⁹ is halo. In otherembodiments, R⁸ and R⁹ are both chloro. In other preferred embodiments,R⁸ and R⁹ are both H. In other preferred embodiments, at least one of R⁸and R⁹ is COOR¹¹ or CONR¹¹ ₂.

In compounds of formula (V), each of m and/or m″ is an integer from 0-3.In certain embodiments, each of m and m″ is 0 or 1. In compounds offormula (V) and (V-A), each Y is independently is halo, OH, or C1-C4alkoxy, or is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C12 aryl, orC6-C14 arylalkyl, or a heteroform of one of these, each of which may beoptionally substituted. In certain embodiments, m is 1 and Y is halo,preferably chloro. In other embodiments, m is 0. In compounds of formula(V) and (V-B), each Y″ is independently is halo, OH, or C1-C4 alkoxy, oris C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14arylalkyl, or a heteroform of one of these, each of which may beoptionally substituted. In certain embodiments, m″ is 1 and Y″ is OH orOMe. In other embodiments, m″ is 0.

In compounds of formula (V), m″ is an integer from 0-3. In certainembodiments, m″ is 0 or 1. In compounds of formula (V), each Y″ isindependently is halo, OH, or C1-C4 alkoxy, or is C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl, or aheteroform of one of these, each of which may be optionally substituted.In certain embodiments, m″ is 1 and Y″ is OH or OMe. In otherembodiments, m″ is 0. In frequent embodiments, each of m and m″ is 0.

In compounds of formula (V), Z is OH, OR, CH₂OR, SR, or NR₂, where eachR is independently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl. In certain embodiments, Z is OH, OMe, OAc,CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc. In preferred embodiments,Z is OH.

In some embodiments of formula (V), R^(10a) and R^(10b) are the same. Inother embodiments, R^(10a) and R^(10b) are different. In certainpreferred embodiments, each of R^(10a) and R^(10b) comprises at leasttwo carbon atoms. For example, each of R^(10a) and R^(10b) mayindependently be ethyl, propyl, isopropyl, allyl, propargyl, n-butyl,s-butyl, isobutyl, t-butyl, pentyl, cyclopropyl, and the like; in somesuch embodiments, R^(10a) and R^(10b) are the same. In a preferredembodiment, each of R^(10a) and R^(10b) is ethyl.

In other embodiments of formula (V), R^(10a) and R^(10b) are takentogether with the carbon to which they are attached to form a C3-C8cycloalkyl or a C3-C8 heterocyclyl ring, which may be optionallysubstituted. For example, R^(10a) and R^(10b) may be taken together toform an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, tetrahydrofuran,tetrahydropyran, tetrahydrothiofuran, tetrahydrothiopyran, pyrrolidine,or piperidine ring, and the like. In a preferred embodiment, each ofR^(10a) and R^(10b) are taken together to form a cyclohexyl or acyclopentyl ring. In some embodiments, the ring formed by R^(10a) andR^(10b) may be fused to a substituted or unsubstituted phenyl ring toprovide, for example, and indenyl or tetrahydronaphthyl ring system.

In specific embodiments of formula (V), the compound has the structureof formula:

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹, R², R⁸, R⁹, Y, Y″, Z, R^(10a) and R^(10b) are defined as forformula (V).

In a preferred embodiment of formula (V), the compound has the formula(V-a) or (V-b) and each of R⁸ and R⁹ is H. In other embodiments offormula (V), the compound has the formula (V-a) or (V-b) and at leastone of R⁸ and R⁹ is chloro. In other preferred embodiments, the compoundhas the formula (V-c), (V-d), (V-e) or (V-f), and Y″ is OH or OMe. Insome such embodiments, each of R⁸ and R⁹ is H. In other embodiments, atleast one of R⁸ and R⁹ is COOR¹¹ or CONR¹¹ ₂.

In another aspect, the invention provides a compound of formula (VI):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹, R², R⁸, R⁹, Y, Y″, m and m″ are defined as for formula (I);

Z is OH, OR, CH₂OR, SR, or NR₂, where each R is independently H,optionally fluorinated C1-C4 alkyl, or optionally fluorinated C1-C4acyl; and

R¹⁰ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl,C3-C8 cycloalkylalkyl, C6-C12 aryl, C6-C20 arylalkyl, or a heteroform ofone of these, each of which may be optionally substituted.

In some embodiments, the compound of formula (VI) has the formula (VI-A)or (VI-B):

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹, R², R⁸, R⁹, Y, Y″, m and m″, Z, and R¹⁰ are defined as forformula (VI).

It will be understood that embodiments of formula (VI) described hereinalso apply to compounds of formula (VI-A) and (VI-B).

In certain embodiments of Formula (VI), R¹ is optionally substitutedC1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; in some such embodiments,R¹ is isopropyl. In some embodiments of formula (VI), R² is H or C1-C4alkyl; sometimes, R² is H or methyl. In certain preferred embodiments,R² is H. In other embodiments, R¹ and R² are taken together with theatoms to which they are attached to form an optionally substituted 5- to7-membered azacyclic ring, optionally containing an additionalheteroatom selected from N, O, and S as a ring member. In specificembodiments, R¹ and R² are taken together to form an optionallysubstituted 5- to 7-membered azacyclic ring containing no additionalheteroatoms, i.e., an optionally substituted pyrrolidine, piperidine orhomopiperidine ring. In other embodiments, R¹ and R² are taken togetherto form an optionally substituted 5- to 7-membered azacyclic ringcontaining an additional heteroatom selected from N, O and S. In somesuch embodiments, R¹ and R² are taken together to form an optionallysubstituted morpholine, thiomorpholine, piperazine, or homopiperazinering.

In some embodiments of formula (VI), R⁸ and R⁹ are independently H,halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C5-C12heteroaryl, each of which may be optionally substituted, or COOR¹¹ orCONR¹¹ ₂, where each R¹¹ is independently H or C1-C4 alkyl. In otherembodiments of formula (VI), (VI-A) and (VI-B), R⁸ and R⁹ areindependently H, halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,C6-C12 aryl, or C5-C12 heteroaryl, each of which may be optionallysubstituted. In certain preferred embodiments, each of R⁸ and R⁹ is H.In certain embodiments, at least one of R⁸ and R⁹ is halo. In otherembodiments, at least one of R⁸ and R⁹ is COOR¹¹ or CONR¹¹ ₂.

In compounds of formula (VI), (VI-A) and (VI-B), each of m and/or m″ isan integer from 0-3. In certain embodiments, each of m and m″ is 0 or 1.In compounds of formula (VI) and (VI-A), each Y is independently ishalo, OH, or C1-C4 alkoxy, or is C1-C8 alkyl, C2-C8 alkenyl, C2-C8alkynyl, C6-C12 aryl, or C6-C14 arylalkyl, or a heteroform of one ofthese, each of which may be optionally substituted. In certainembodiments, m is 1 and Y is halo, preferably chloro. In otherembodiments, m is 0. In compounds of formula (VI) and (VI-B), each Y″ isindependently is halo, OH, or C1-C4 alkoxy, or is C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl, or aheteroform of one of these, each of which may be optionally substituted.In certain embodiments, m″ is 1 and Y″ is OH or OMe. In otherembodiments, m″ is 0.

In compounds of formula (VI), m″ is an integer from 0-3. In certainembodiments, m″ is 0 or 1. In compounds of formula (VI), each Y″ isindependently is halo, OH, or C1-C4 alkoxy, or is C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl, or aheteroform of one of these, each of which may be optionally substituted.In certain embodiments, m″ is 1 and Y″ is OH or OMe. In otherembodiments, m″ is 0. In frequent embodiments, each of m and m″ is 0.

In compounds of formula (VI), Z is OH, OR, CH₂OR, SR, or NR₂, where eachR is independently H, optionally fluorinated C1-C4 alkyl, or optionallyfluorinated C1-C4 acyl. In certain embodiments, Z is OH, OMe, OAc,CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc. In preferred embodiments,Z is OH.

In some embodiments of formula (VI), R¹⁰ is C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12 aryl,C6-C20 arylalkyl, or a heteroform of one of these, each of which may beoptionally substituted. For example, R¹⁰ may be ethyl, propyl,isopropyl, allyl, propargyl, n-butyl, s-butyl, isobutyl, t-butyl,pentyl, cyclopropyl, and the like.

In specific embodiments of formula (VI), the compound has the formula:

or a pharmaceutically acceptable salt or conjugate thereof;

wherein R¹, R², R⁸, R⁹, Y, Y″, Z, and R¹⁰ are defined as for formula(VI).

The present invention specifically excludes the compounds of formula:

Where chiral carbons are included in chemical structures, unless aparticular orientation is depicted, both stereoisomeric forms areintended to be encompassed. Compounds of formulae (I), (II), (III),(IV), (V) and (VI) may, for example, have two or more asymmetric centersand therefore exist in different enantiomeric and/or diastereomericforms. All optical isomers and stereoisomers of the compounds describedherein, and mixtures thereof, are considered to be within the scope ofthe invention, including the racemate, one or more enantiomeric forms,one or more diastereomeric forms, or mixtures thereof. In particular,racemic mixtures of single diastereomers such as the ones described,diastereomers having an diastereomeric excess (d.e.) of greater than 90%or greater than about 95%, and enantiomers having an enantiomeric excess(e.e.) of greater than 90% or greater than about 95%. Similarly, wheredouble bonds are present, the compounds can exist in some cases aseither cis or trans isomers; the invention includes each isomerindividually as well as mixtures of isomers. Where the compoundsdescribed may also exist in tautomeric forms, this invention relates tothe use of all such tautomers and mixtures thereof.

Compounds of formulae (I), (II), (III), (IV), (V) and (VI) can besupplied in free base form, or can be supplied as a pharmaceuticallyacceptable salt, or as a mixture of the free base form and thecorresponding salt. The compounds of the invention may be isolated assalts where an ionizable group such as a basic amine or a carboxylicacid is present. The invention includes the salts of these compoundsthat have pharmaceutically acceptable counterions. Such salts are wellknown in the art, and include, for example, salts of acidic groupsformed by reaction with organic or inorganic bases, and salts of basicgroups formed by reaction with organic or inorganic acids, as long asthe counterions introduced by the reaction are acceptable forpharmaceutical uses. Examples of inorganic bases with alkali metalhydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkalineearth metal hydroxides (e.g., of calcium, magnesium, etc.), andhydroxides of aluminum, ammonium, etc. Examples of organic bases thatcould be used include trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, etc.

Suitable salts include those of inorganic acids such as hydrochlorides,hydrobromides, sulfates, hydrosulfates, and the like, or organic acidaddition salts. Examples of inorganic acids that could be used includehydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc. Examples of organic acids include formic acid,oxalic acid, acetic acid, tartaric acid, methanesulfonic acid,benzenesulfonic acid, malic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc. Also included are salts with basicamino acids such as arginine, lysine, ornithine, etc., and salts withacidic amino acids such as aspartic acid, glutamic acid, etc.

In addition, compounds of formulae (I), (II), (III), (IV), (V) and (VI)may be coupled to moieties such as targeting agents. Among suchtargeting agents are antibodies or immunologically active fragmentsthereof, including single-chain antibody forms directed against tumorantigens or against receptors or integrins associated with tumors,peptidomimetics directed against these moieties, and the like. Inaddition, compounds of formulae (I), (II), (III), (IV), (V) and (VI) maybe coupled to an excipient such as polyethylene glycol for alteringpharmacokinetics. The selected PEG may be of any convenient molecularweight, and may be linear or branched, and may be optionally conjugatedthrough a linker. The average molecular weight of PEG will preferablyrange from about 2 kiloDalton (kDa) to about 100 kDa, more preferablyfrom about 5 kDa to about 40 kDa.

Compounds of formulae (I), (II), (III), (IV), (V) and (VI) are useful intreating or ameliorating cell proliferative diseases. In particular, thecompounds and methods described herein are useful for the treatment oramelioration of tumors and malignancies associated with breast, ovary,lung (SCLC and NSCLC), colon, rectum, prostate, testes, skin (e.g.,melanoma, basal cell carcinoma, and squamous cell carcinoma), pancreas,liver, kidney, brain (e.g., glioma, meningioma, schwannomas, andmedulloblastomas), and the blood and hematopoietic system, including,e.g., leukemia, non-Hodgkins lymphoma, and multiple myeloma.

In the methods described herein, for example, cell proliferation may bereduced, and/or cell death, such as apoptosis or apoptotic cell death,may be induced. The cell proliferative disorder may be a tumor ornon-tumor cancer in a human or animal subject.

The compounds and methods provided herein for reducing cellproliferation and/or inducing cell death may be used alone, or inconjunction with or in combination with surgical, radiation,chemotherapeutic, immunotherapy, and bone marrow and/or stem celltransplantation methods, or with other palliative agents, such ascompounds that aid in nutrition or general health, anti-emetic agents,and the like.

In some embodiments, the compounds of the present invention areadministered in combination with a chemotherapeutic agent, and used toreduce cell proliferation, induce cell death, and/or treat or amelioratea cell proliferative disorder.

The compounds described herein are also useful against certain drugresistant tumors and cancer cell lines, in particular against cancersthat are resistant to TAXOL® and/or vinca alkaloid anti-cancer agents.

Where an additional chemotherapeutic drug is administered, it istypically one known to have cytostatic, cytotoxic or antineoplasticactivity. These agents include, without limitation, antimetabolites(e.g., cytarabine, fludaragine, 5-fluoro-2′-deoxyuridine, gemcitabine,hydroxyurea, methotrexate); DNA active agents (e.g., bleomycin,chlorambucil, cisplatin, cyclophosphamide); intercalating agents (e.g.,adriamycin and mitoxantrone); protein synthesis inhibitors (e.g.,L-asparaginase, cycloheximide, puromycin); topoisomerase type Iinhibitors (e.g., camptothecin, topotecan or irinotecan); topoisomerasetype II inhibitors (e.g. etoposide, teniposide anthraquinones,anthracyclines and podophyllotoxin); microtubule inhibitors (e.g.,taxanes, such as paclitaxel and docetaxel, colcemid, colchicines, orvinca alkaloids, such as vinblastine and vincristine); kinase inhibitors(e.g. flavopiridol, staurosporin and hydroxystaurosporine), drugs thataffect Hsp90 (e.g. geldanomycin and geldanomycin derivatives, radicicol,purine derivatives and antibodies or antibody fragments that selectivelybind to Hsp90), TRAIL, a TRAIL receptor antibody, TNF-α or TNF-β, and/orradiation therapy.

In some preferred embodiments, the additional cancer therapeutic agentis TRAIL, a TRAIL receptor antibody, TNF-α or TNF-β. In other preferredembodiments, the additional drugs for co-administration with thecompounds of the invention affects Hsp90 (heat-shock protein 90).

Suitable Hsp90 inhibitors include ansamycin derivatives such asgeldanomycin and geldanomycin derivatives including17-(allylamino)-17-desmethoxygeldanamycin (17-AAG), its dihydroderivative, 17-AAGH₂, and 17-amino derivatives of geldanamycin such as17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG),11-oxogeldanamycin, and 5,6-dihydrogeldanamycin, which are disclosed inU.S. Pat. Nos. 4,261,989; 5,387,584; and 5,932,566, each of which isincorporated herein by reference. Other suitable Hsp90 inhibitorsinclude radicicol and oximes and other analogs thereof, disclosed inSoga, et al., Curr. Cancer Drug Targets, 3, 359-69 (2003), and inYamamoto, et al., Angew. Chem., 42, 1280-84 (2003); and in Moulin, etal., J. Amer. Chem. Soc., vol 127, 6999-7004 (2005); purine derivativessuch as PU3, PU24FCI and PUH64 (see Chiosis et al., ACS Chem. Biol. Vol.1(5), 279-284 (2006) and those disclosed in PCT Application No. WO2002/0236075; related heterocyclic derivatives disclosed in PCTApplication No. WO 2005/028434; and 3,4-diarylpyrazole compoundsdisclosed in Cheung, et al., Bioorg. Med. Chem. Lett., vol. 15, 3338-43(2005). Antibodies or antibody fragments that selectively bind to Hsp90may also be administered as drugs to cause inhibition of Hsp90, and canbe used in combination with the compounds of the invention.

Where a compound described herein is utilized in conjunction with or incombination with another therapeutic, the two agents may beco-administered, or they may be administered separately where theiradministration is timed so the two agents act concurrently orsequentially.

Accordingly, the compositions used in the methods described hereininclude at least one compound of the invention, and can optionallyinclude one or more additional cytotoxic or cytostatic therapeutic suchas, but not limited to, those disclosed above. Similarly, the methods ofthe invention include methods wherein a subject diagnosed as in need oftreatment for cancer is treated with at least one compound orcomposition of the invention, and is simultaneously or concurrentlytreated with one or more of the additional therapeutic agents describedabove.

Formulation and Administration

The formulations useful in the invention include standard formulationssuch as those set forth in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Co., Easton, Pa., incorporated herein byreference. Such formulations include those designed for oral delivery,slow release, topical administration, parenteral administration, or anyother suitable route as determined by an attending physician orveterinarian. Thus administration may be systemic or local. Suitablevehicles or excipients include liposomes, micelles, nanoparticles,polymeric matrices, buffers, and the full range of formulations known topractitioners.

Formulations of the compounds and compositions of the invention may beprepared in a manner suitable for systemic administration or topical orlocal administration. Systemic formulations include those designed forinjection (e.g., intramuscular, intravenous or subcutaneous injection)and those prepared for transdermal, transmucosal, or oraladministration. The formulation will generally include a diluent as wellas, in some cases, adjuvants, buffers, preservatives and the like. Thecompounds can be administered also in liposomal compositions or asmicroemulsions.

Injection methods are sometimes appropriate routes for administration ofthe compounds for systemic treatments and sometimes also for localizedtreatments. These include methods for intravenous, intramuscular,subcutaneous, and other methods for internal delivery that bypass themucosal and dermal barriers to deliver the composition directly into thesubject's living tissues.

For injection, formulations can be prepared in conventional forms asliquid solutions or suspensions or as solid forms suitable for solutionor suspension in liquid prior to injection or as emulsions. Suitableexcipients include, for example, water, saline, dextrose, glycerol andthe like. Such compositions may also contain amounts of nontoxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents and the like, such as, for example, sodium acetate, sorbitanmonolaurate, and so forth.

Various sustained release systems for drugs have also been devised andcan be utilized with the compounds of the invention. See, for example,U.S. Pat. No. 5,624,677. The present compositions can be utilized insuch controlled-release delivery systems where appropriate.

Systemic administration may also include relatively noninvasive methodssuch as the use of suppositories, transdermal patches, transmucosaldelivery and intranasal administration. Oral administration is alsosuitable for compounds of the invention. Suitable forms include syrups,capsules, tablets, and the like as in understood in the art.

Selection of a particular route of administration for a given subjectand indication is well within the ordinary level of skill in the art.For example, rectal delivery as a suppository is often appropriate wherethe subject experiences nausea and vomiting that precludes effectiveoral delivery. Transdermal patches are commonly capable of delivering acontrolled-release dosage over several days or to a specific locus, andare thus suitable for subjects where these effects are desired.

Transmucosal delivery may also be appropriate for some of thecompositions and methods of the invention. Thus the compositions of theinvention may be administered transmucosally using technology andformulation methods that are known in the art.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of the present invention may be varied so as to obtain anamount of the active ingredient which is effective to achieve thedesired therapeutic response for a particular patient, composition, andmode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or salt or conjugate thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

For administration to animal or human subjects, the dosage of a compoundof the invention is typically 1-2400 mg per administration. However,dosage levels are highly dependent on the nature of the condition, thecondition of the patient, the judgment of the practitioner, and thefrequency and mode of administration. Selection of a dosage of suchcompounds is within the skill of an ordinary artisan, and may beaccomplished by starting at a relatively low dosage and increasing thedosage until an acceptable effect is achieved.

Frequency of administration of the compounds of the invention can alsobe readily determined by one skilled in the art using well knowntechniques. For example, the patient may be administered a low dosage ofa compound or composition of the invention at a low frequency such asonce per day or less often; and the dosage and/or frequency ofadministration may be systematically increased until a desired effect isachieved in the patient.

Synthetic Processes

Diazonamide analogs of formula (I) were prepared through a novel andefficient multi-step process, as shown in Scheme 1 and Scheme 2 andexemplified throughout the Examples. A key step in the process offorming the macrocyclic structure of these compounds involved theelectrochemical oxidative cyclization of a phenolic intermediate toprovide the macrocyclic indoline intermediate. This transformation hasbeen described in U.S. application Ser. No. 12/134,984, filed Jun. 6,2008, published as US 2009/0005572, the contents of which areincorporated herein by reference in their entirety.

As shown in Scheme 1, dipeptide starting materials were prepared understandard conditions known in the art, for example, by coupling anN-hydroxysuccinimide ester or another activated ester of a protectedamino acid with serine. It will be understood by one of skill in the artthat a wide variety of suitable conditions may be utilized to form thedipeptide starting materials, including the extensive body of literaturedescribing synthesis of peptides and peptide mimetics.

The dipeptide was reacted with an optionally substituted indole and anactivating reagent, optionally in the presence of a protic acid, toprovide an indole-containing dipeptide. Suitable activating reagentsinclude, for example, carboxylic acid anhydrides, mixed anhydrides, oracyl halides (e.g., acetic anhydride, trifluoroacetic anhydride, acetylchloride, oxalyl chloride), sulfonic acid anhydrides or halides (e.g.,methanesulfonic anhydride, trifluoromethanesulfonic anhydride,methanesulfonyl chloride), mineral acid halides (e.g., thionyl chloride,or phosphoryl chloride), and the like.

In a preferred embodiment, the activating agent was acetic anhydride,and the reaction was conducted in acetic acid as a protic solvent. In aparticularly preferred embodiment, the dipeptide and an optionallysubstituted indole were reacted with acetic anhydride in acetic acid atabout 80° C., to provide the desired compound.

The preparation of N-acetyl tryptophan derivatives by reaction of serineor N-acetyl serine and an optionally substituted indole in aceticanhydride and acetic acid has been previously reported. Y. Yokoyama, etal., Tetrahedron Letters (1999), 40: 7803; Y. Yokoyama, et al., Eur. J.Org. Chem. (2004), 1244; Y. Konda-Yamada, et al., Tetrahedron (2002),58: 7851; M. W. Orme, et al., U.S. Pat. No. 6,872,721. However, thepreparation of other acylated tryptophan derivatives under theseconditions, such as the dipeptide analogs of the present invention, hasnot been described to our knowledge.

Esterification of the free carboxylic acid, followed by oxidativecyclization of the dipeptide intermediate with an oxidizing agent, forexample, DDQ, provided an oxazole intermediate. It will be understood bythose in the art that other oxidative conditions could be utilized, suchas, for example, 7,7,8,8-tetracyanoquinodimethane (TCNQ), ceric ammoniumnitrate, hypervalent iodide reagents, and the like.

Deprotection of the protected amino group and amide bond formationprovided a phenolic intermediate. Electrochemical oxidative cyclizationof the phenolic intermediate provided a macrocyclic indoline compound.Such compounds can be further elucidated to compounds of formula (I). Arepresentative synthesis is shown in Scheme 2. Deprotection of thecarboxylate ester followed by amide bond formation installed the indolering. Cyclization to provide an oxazole intermediate, followed by anoxidative photochemical cyclization provided macrocyclic intermediates.Straightforward functional group manipulations provide compounds offormula (I). Following removal of the phenolic group used to direct thecyclization, the Cbz protecting group was removed. Standard functionalgroup reactions, such as for example by acylation, amide coupling,sulfonylation, alkylation, reductive alkylation, and the like, may beused to install the substituents at R⁴ and/or R⁵.

Those skilled in the art will appreciate that certain reactionconditions can be varied without altering the essence of the presentinvention. For example, coupling reactions can be accomplished with avariety of activated esters, such as by way of example onlyN-hydroxybenzotriazole ester, perfluorophenyl ester,N-hydroxyphthalimide esters, activated esters generated by the reactionof the carboxylic acid with a carbodiimide, and other activated estersconventionally used for acylation of an amine to form amide bonds. Itwill be understood by one of skill in the art that the representativeroutes shown may be modified, for example by the use of differentprotecting groups on the amine, indole, and/or indoline nitrogen atoms,or on functionality present elsewhere in the molecule (for example, assubstituent Y). Suitable protecting groups and methods to attach andremove them are well known in the art, and are described, for example,in T. H. Greene, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2^(nd) ed.

The selection of orthogonal protecting groups for polyfunctionalmolecules is known in the art. In the present methods, while aminogroups are conveniently protected as carbobenzyloxy (Cbz) group, one ofskill in the art will recognize that other suitable protecting groupscould be utilized. It will be further understood that the methods shownherein include an optional deprotection step or steps to removeprotecting groups present in the molecules. It will be understood by oneof skill in the art that compounds of formulae described herein can beprepared by modification of Schemes 1 and 2, for example by deprotectionof the protected amine in Scheme 2 and amide bond formation to installan appropriate acyl substituent, for example, the group —C(O)R³ or—C(O)C(Z)R^(10a)R^(10b) or —C(O)CH(Z)R¹⁰ at R⁵ in formula (I).

Compound of the formulae described herein are available in high yieldand purity. In particular, the compounds of the present invention areavailable in good yield and with high diastereomeric purity, preferablyin greater than 95% diastereomeric excess, sometimes greater than 98%diastereomeric excess.

Mass spectrometry (MS) was conducted with various techniques. Massspectra were typically obtained using liquid chromatograph electrosprayionization mass spectrometry, MS (ESP).

The following examples are offered to illustrate but not to limit theinvention.

Example 1 7-Bromoindole

2-Bromonitrobenzene (1.10 kg, 5.45 mol) was dissolved in THF (10 L) atRT. This solution was cooled with stirring in a bath maintained at −78°C. When the internal temperature reached −40° C., vinylmagnesium bromide(16.3 L, 16.3 mol) was added at such a rate as to maintain the internaltemperature at −40° C. during the addition. Upon complete addition, thereaction was removed from the bath and allowed to warm slowly to −30° C.over the course of 45 min. This required occasional cooling. The −30° C.reaction solution was quenched by rapid addition of a slightly cool(˜10° C.) solution of saturated aqueous NH₄Cl (10 L). Slight foamingoccurred (inverse quench into the NH₄Cl solution is also satisfactory).This resulted in a biphasic mixture with some undissolved magnesiumsalts in the form of a gel. The mixture was stirred for 30 min and thelayers were separated. The aqueous layer was back extracted with THF (10L). The combined organic layers were evaporated at reduced pressure witha bath temperature of 35° C. and the resulting dark oil was taken up inCH₂Cl₂ (5 L) and dried with Na₂SO₄. The mixture was filtered andconcentrated. The resulting material was chromatographed, eluting with2% EtOAc-hexanes to give 7-bromoindole (557 g, 52% yield) as anoff-white solid. ¹H NMR (CDCl₃): consistent with proposed structure.

Example 2 Cbz-Val-Ser-OH

L-Serine (104.19 g, 991 mmol) was dissolved in water (1440 mL) in a 4-LErlenmeyer flask. Solid NaHCO₃ (83.25 g, 991 mmol) was added and themixture was stirred at RT to give a clear solution. Cbz-Val-OSu (300.0g, 861 mmol) was added as a solution in 1,4-dioxane (1500 mL), withadditional 1,4-dioxane (220 mL) used to rinse. The resulting cloudymixture became clear after 1.5 h of stirring at 25° C. After 44 h, themixture was divided into two equal portions. Methanol (700 mL) and 12 Naqueous HCl (42 mL, 504 mmol) were added to each portion, followed byEtOAc (1000 mL) and a solution of NaCl (100 g) dissolved in water (600mL). The layers were separated and the organic layer was washed withsaturated aqueous NaCl (350 mL). The aqueous layers were extracted insuccession with EtOAc (1000 mL). The organic layers resulting fromwork-up of both portions of the reaction were combined, dried (Na₂SO₄),filtered, and evaporated to give a white solid (351 g). This materialwas suspended in CH₂Cl₂ (1500 mL) and stirred for 2 h. The mixture wasfiltered and the crystals were washed with CH₂Cl₂ (1000 mL) to giveCbz-Val-Ser-OH as white crystals (262.3 g, 90% yield). ¹H NMR (300 MHz,DMSO-d₆): consistent with proposed structure. MS: m/z=339.1 (M+1).

Example 3 Cbz-Val-(7-Bromo-Trp)-OH

Acetic acid (180 mL) was added to Cbz-Val-Ser-OH (42.89 g, 127 mmol)from Example 2 and 7-bromoindole (30.96 g, 158 mmol) from Example 1 in around-bottom flask fitted with a mechanical stirrer, reflux condenser,and internal thermometer. Acetic anhydride (40 mL, 43 g, 420 mmol) wasadded and the mixture was heated to 80° C. over 40 min. Heating wascontinued at this temperature for 4 h. After cooling to RT and standingovernight, the mixture was diluted with ethyl ether (180 mL) and stirredfor 30 min. The mixture was filtered and the crystals were washed withethyl ether (250 mL). Drying of the crystals yieldedCbz-Val-(7-bromo-Trp)-OH (42.49 g, 65% yield). ¹H NMR (300 MHz,DMSO-d₆): consistent with proposed structure. MS: m/z=516.0 (M+1).

Example 4 Cbz-Val-(7-Bromo-Trp)-OMe

Concentrated aqueous HCl (60 mL, 720 mmol) was added to a stirredsuspension of Cbz-Val-(7-bromo-Trp)-OH (32.53 g, 63.0 mmol) from Example3 in 2,2-dimethoxypropane (1200 mL, 1020 g, 9.8 mol). After stirring for24 h at 25° C., most of the solvent was evaporated to give wet crystals.MTBE (250 mL) was added and the mixture was allowed to stand withoccasional swirling over 3 h. Filtration and washing of the crystalswith MTBE (100 mL) gave Cbz-Val-(7-bromo-Trp)-OMe (30.31 g, 91% yield).¹H NMR (300 MHz, DMSO-d₆): consistent with proposed structure. MS:m/z=530.1 (M+1).

Example 5 Methyl2-((S)-1-(benzyloxycarbonylamino)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate

A solution of DDQ (28.41 g, 125 mmol) in THF (251 g, 282 mL) was addedto Cbz-Val-(7-bromo-Trp)-OMe (30.20 g, 56.9 mmol) from Example 4 in THF(848 g, 954 mL) and the dark solution was heated to gentle reflux in anoil bath at 85° C. for 6 h. After cooling and standing overnight at RT,the solvent was removed on a rotary evaporator. Methanol (200 mL) wasadded and the solvent was evaporated to leave a brown crusty solid (91g). Methanol (200 mL) was added and the solid was loosened with aspatula. The mixture was swirled until the appearance changed to a redliquid containing a yellow precipitate. The mixture was filtered and theprecipitate was washed with methanol (60 mL). The pale gray crystalswere air dried and then dried under vacuum to give methyl24(S)-1-(benzyloxycarbonylamino)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate(17.98 g, 60% yield). ¹H NMR (300 MHz, DMSO-d₆): consistent withproposed structure. MS: m/z=526.0 (M+1).

Example 6 Methyl2-((S)-1-amino-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylatehydrobromide

Glacial acetic acid (25 mL) was added to methyl2-((S)-1-(benzyloxycarbonylamino)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate(9.99 g, 19.0 mmol) in a 500-mL round-bottom flask fitted with amechanical stirrer. The suspension was stirred at 25° C. and 33% HBr inacetic acid (50 mL) was added in one portion. The mixture becamehomogeneous and then a precipitate formed in 5-10 min. After 1 h, MTBE(235 mL) was added and stirring was continued at 25° C. for another 1 h20 min. The mixture was filtered and the precipitate was washed withMTBE (150 mL). The cream-colored powder was dried under vacuum to givemethyl2-((S)-1-amino-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylatehydrobromide (8.91 g, 99% yield). ¹H NMR (300 MHz, DMSO-d₆): consistentwith proposed structure. MS: m/z=392.0 (M+1).

Example 7 Methyl2-((S)-1-((S)-2-(benzyloxycarbonylamino)-3-(4-hydroxyphenyl)propanamido)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate

DMF (100 mL) was added to methyl2-((S)-1-amino-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylatehydrobromide (9.16 g, 19.4 mmol), HOBt (3.17 g, 23.5 mmol), andCbz-Tyr-OH (6.44 g, 20.4 mmol) in a round-bottom flask.N,N-Diisopropylethylamine (4.22 mL, 3.13 g, 129 mmol) was added,followed by EDC (4.15 g, 21.6 mmol). After stirring for 24 h at 25° C.,the solution was diluted with EtOAc (500 mL) and the mixture was washedwith 1 N aqueous HCl (250 mL), saturated aqueous NaHCO₃ (250 mL), andsaturated aqueous NaCl (250 mL). The solution was dried (Na₂SO₄),decanted, and evaporated to give a tan solid. This material wasdissolved in 2-PrOH (180 mL) at 90° C. Hexanes (85 mL) were added andthe solution was allowed to cool to RT. After standing overnight, themixture was cooled to 5° C. for 4 h. The solid was separated byfiltration and washed with 1:1 2-PrOH/hexanes (140 mL). This material,which at this point held residual solvent, was dried on a vacuummanifold to give methyl2-((S)-1-(S)-2-(benzyloxycarbonylamino)-3-(4-hydroxyphenyl)propanamido)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate(11.58 g, 87% yield). ¹H NMR (300 MHz, DMSO-d₆): consistent withproposed structure. MS: m/z=689.0 (M+1).

Example 8

An electrochemical cell was assembled using a polyethylene cylinder (15cm diameter×30 cm height) and a custom rack (polypropylene and nylon)which supported 48 vertical graphite rods (6.15 mm diameter×30 cmlength). The rods were arranged in a pattern of three concentric ringswith 12 and 24 anodes in the inner and outer rings, respectively. Theintermediate ring contained 12 cathodes, separated from adjacent anodesby approximately 7 mm Electrodes were immersed to a depth of 24 cm. Thephenolic material synthesized in Example 7 (20.00 g, 29.0 mmol) andEt₄NBF₄ (70.00 g, 322 mmol) were dissolved in DMF (4000 mL), and KOH(˜86%, 1.68 g, 26 mmol) was added in 10 mL of water. The solution wasstirred vigorously by two 4-bladed turbines (50 mm diameter, blades at45°, approx. 680 rpm) on a single shaft. The electrochemical reactionwas carried out at a potential of 1.5-1.6 volts. Additional phenolicstarting material (20.00 g, 20.00 g, 20.00 g, and 7.94 g) was added as asolid, along with KOH (˜86%, 1.60 g, 1.63 g, 1.53 g, and 0.65 g) inwater (5.0 mL, 5.0 mL, 5.0 mL, and 2.0 mL) on days 3, 5, 8, and 10,respectively. After 13 days, approximately 27.7 amp-h of current hadpassed, and 5.8% of the original SM remained as determined by HPLCintegration at 220 nM. The reaction mixture was concentrated on a rotaryevaporator (bath temp. ≦35° C.) and dried further on a vacuum manifold.The residue was partitioned between EtOAc (1200 mL) and 0.5 N aqueousHCl (600 mL). The organic layer was washed with saturated aqueous NaHCO₃(250 mL) and then saturated aqueous NaCl (250 mL). The aqueous layerswere extracted in succession with EtOAc (2×250 mL). The combined organiclayers were dried (Na₂SO₄), decanted and evaporated to give 70.1 g ofcrude product. This material was purified by flash column chromatographyin three portions. Each portion used silica gel (283 g) with 25% EtOAcin CH₂Cl₂ (approx. 2.4 L for packing column and elution). This yielded35.6 g (41% yield) of product as a mixture of stereoisomers (83.5:13.6as measured by HPLC integration at 220 nM). MTBE (500 mL) was added andthe mixture was stirred at RT for 2 h. After standing an additional 3 h,the mixture was filtered and the solid was washed with MTBE (3 portions,100 mL total). HPLC analysis of the filtrate showed 94.8% purity(94.8:2.1 stereoisomer ratio measured by integration at 220 nm). Thefiltrate was evaporated and the resulting residue was dried under vacuumto yield 31.99 g of product (36% yield) of as a pale yellow solid. MS:m/z=687.0 (M+1).

Example 9

To a three-neck round-bottom flask equipped with a thermometer, anaddition funnel and a magnetic stir bar was added the methyl estersynthesized in Example 8 (530 mg, 0.77 mmol) and methanol (18 mL). Thesolution was cooled to 0° C. in an ice-water bath followed by additionof LiOH in water (324 mg/5 mL, 7.7 mmol) at 0° C. with stirring. Afterthe addition the reaction mixture became a slurry. The cooling bath wasremoved and the mixture was allowed to warm to RT. The precipitatedisappeared gradually. After 4.5 h stirring at RT less than 2% of SMremained as determined by LCMS. Ice (40 g) was added to the reactionmixture and 1 N aqueous HCl (10 mL) was added dropwise from an additionfunnel with vigorous stirring to acidify the 0° C. reaction mixture. ThepH of the mixture was adjusted to 2.5-3.0. A pale yellow solidprecipitated, which was extracted using EtOAc (2×50 mL). The aqueousphase was concentrated to remove most of the methanol and then extractedwith EtOAc (2×50 mL). The combined organic layers was dried over Na₂SO₄and concentrated to afford crude product (516 mg, 0.77 mmol, ca. 96%pure and containing by-product hydantoin) which was used directly in thenext step without further purification. MS: m/z=673.2 (M+1).

Example 10

To a dry 250-mL round-bottom flask with magnetic stir bar was addedDHOBt (545 mg, 3.34 mmol), EDC (2.75 g, 14.32 mmol), anhydrous DMF (130mL) and TEA (2.0 mL, 14.32 mmol). The resulting reagent mixture wasstirred for 20 min. To another dry 500-mL round-bottom flask was addedthe crude product from Example 9 (6.43 g, 9.6 mmol),2-amino-1-(7-hydroxy-1H-indol-3-yl)ethanone hydrochloride (3.25 g, 14.32mmol) and DMF (30 mL). Then TEA (2.0 mL, 14.32 mmol) was added dropwisefollowed by the addition of the reagent mixture above. The resultingreaction mixture was stirred for 6 h at 40-42° C. and cooled to RTovernight. About 4% of starting acid remained as determined by LCMS.Most of DMF was removed under vacuum at 45° C. Less than 1% of startingmaterial remained. The residue was diluted with EtOAc (800 mL)/water(200 mL). Some undissolved brown solid was removed by filtration. Theorganic phase was separated and the aqueous phase was extracted by EtOAc(2×100 mL). The combined organic layers were washed with water (100 mL),10% aqueous NaHSO₄ (100 mL), water (100 mL), saturated NaHCO₃ (100 mL),water (2×100 mL) and brine (100 mL), and then dried over Na₂SO₄. Afterconcentration the crude product (8.4 g, 9.6 mmol) was obtained and useddirectly in next step without further purification. ¹H NMR (400 MHz,CDCl₃): consistent with proposed structure. MS: m/z=845.1 (M+1).

Example 11

To a dry 500-mL flask containing crude product from Example 10 (8.4 g,9.6 mmol) was added anhydrous THF (40 mL) and anhydrous CH₂Cl₂ (150 mL).The resulting solution was cooled to 0° C. in an ice-water bath. Aceticanhydride (2.69 mL, 28.65 mmol) and pyridine (1.16 mL, 14.33 mmol) wereadded sequentially at 0° C. Then the mixture was allowed to warm to RTand stirred under N₂. The reaction was monitored using LCMS. After 3.5 honly 2% of starting material was not consumed and 2% of over-acetylatedproduct was formed. The reaction solution was diluted with EtOAc (700mL) followed by washing with water (3×100 mL) and brine (100 mL) anddrying over Na₂SO₄. After concentration, the crude compound product waspurified by flash chromatography eluting with a EtOAc-CH₂Cl₂ gradient(30/70 to 35/65) to afford desired product (4.56 g, 5.14 mmol, 51% yieldover three steps). ¹H NMR (400 MHz, CDCl₃): consistent with proposedstructure. MS: m/z=887.1 (M+1).

Example 12

Triphenylphosphine (13.48 g, 51.4 mmol) and hexachloroethane (12.17 g,51.4 mmol) were added to a dry 1-L three-neck round-bottom flaskequipped with a thermometer, an addition funnel and a magnetic stir bar.Anhydrous CH₂Cl₂ (320 mL) was added and the resulting solution wascooled to 10° C. in an ice-water bath under N₂. TEA (10.03 mL, 71.96mmol) was added slowly to the solution, followed by stirring for 10 minat 10° C. The solution of the product from Example 11 (4.56 g, 5.14mmol) in anhydrous CH₂Cl₂ (160 mL) was added dropwise over 5 min and thetemperature was kept at 10-12° C. The reaction mixture was stirred at10° C. for another 10 min, and TLC showed that no starting materialleft. The reaction mixture was cooled to −30° C. followed by addition ofphosphate buffer (200 mL, pH=6.9, 0.5 M) to consume excess reagents. Theresulting reaction mixture was stirred in cold room (4° C.) for 48 h.Most of triphenylphosphine was consumed as determined by LCMS. Theorganic phase was separated and the aqueous phase was extracted byCH₂Cl₂ (2×100 mL). Combined organic phase was washed with water (100 mL)and brine (100 mL) and dried over Na₂SO₄. All solvent was removed underreduced pressure on a rotary evaporator followed by the addition ofEtOAc (40 mL) to precipitate triphenylphosphine oxide. After filteringand washing with CH₂Cl₂, the filtrate was concentrated. The crudecompound was purified by flash chromatography eluting with EtOAc/toluene(60/40; column 4×28 cm) to give desired compound (3.41 g, 3.92 mmol, 76%yield). ¹H NMR (400 MHz, CDCl₃): consistent with proposed structure. MS:m/z=869.1 (M+1).

Example 13

The solution of the product from Example 12 (1.2 g, 1.38 mmol) inacetonitrile (400 mL) was added to a 500-mL flask of a Hanoviaphotoreactor in a photochemical safety cabinet. The solution wasdegassed by a stream of argon for 30 min. Then a pre-degassed aqueoussolution of lithium hydroxide (83 mg/70 mL, 3.45 mmol) was added bysyringe. The resulting solution was degassed again for another 1 h. Thedoor of cabinet was closed. Then the water flow (for cooling the UVlamp) was turned on and UV lamp (with Pyrex filter) was turned on. Thereaction solution was irradiated with UV for 120 min followed byquenching with 70 mL of saturated NH₄Cl. The organic phase was separatedand the aqueous phase was extracted with EtOAc (2×100 mL). The combinedorganic phase was washed with brine (100 mL) and dried over Na₂SO₄. Thisphotoreaction protocol was performed three times using a total of 3.41 g(3.92 mmol) of starting material. All crude product was combined andpurified by flash chromatography eluting with an EtOAc-CH₂Cl₂ gradient(40:60 to 55:45) to afford desired product (1.29 g, 1.72 mmol, 44%yield). ¹H NMR (400 MHz, CDCl₃): consistent with proposed structure. MS:m/z=747.2 (M+1). Deacetylated starting material (865 mg, 1.05 mmol, 27%yield) was recovered.

Example 14

To a dry 250-mL two-neck round-bottom flask equipped with a thermometercontaining the product from Example 13 (1.29 g, 1.72 mmol) was addedanhydrous CH₂Cl₂ (100 mL) and TEA (0.719 mL, 5.16 mmol). The suspensionwas cooled to 0° C. in an ice-brine bath followed by addition of thesolution of trifluoromethanesulfonic anhydride (0.407 mL, 2.41 mmol) inanhydrous CH₂Cl₂ (14 mL) dropwise at 0° C. The mixture was stirred at 0°C. under N₂ for 2 h and TLC showed that all starting material wasconsumed. Saturated NaHCO₃ (20 mL) was added to quench the reaction. Theorganic phase was separated, washed with water (30 mL) and brine (2×30mL) and dried over Na₂SO₄. The solution was concentrated to afford thecrude product (1.50 g, 1.71 mmol) which was used directly in next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃): consistent withproposed structure. MS: m/z=879.2 (M+1).

Example 15

To a 250-mL round-bottom flask containing crude product from Example 14(1.47 g, 1.67 mmol) was added methanol (75 mL) and TEA (0.838 mL, 6.0mmol). The flask was purged with N₂ flow for 10 min followed by additionof 20% Pd(OH)₂/C (2.64 g) under N₂. A H₂ balloon was attached and theflask was purged with H₂ four times. Then the H₂-filled balloon wasopened to the reaction system. After 6.5 h stirring about 5% of startingmaterial remained. The reaction was stopped. The reaction mixture wasfiltered through a pad of Celite® and the black cake was washed withmethanol (5×15 mL). The filtrate was concentrated and the residue wasdissolved in CH₂Cl₂ (500 mL). The resulting solution was washed withwater (3×100 mL) and brine (100 mL), and dried over Na₂SO₄. The solutionwas concentrated to afford the crude product (930 mg, 1.56 mmol) whichwas used directly in next step without further purification. ¹H NMR (400MHz, CD₃OD): consistent with proposed structure. MS: m/z=597.2 (M+1).

Example 16

Compound J (Reference Example)

To a dry 100-mL round-bottom flask containing the product from Example15 (930 mg, 1.56 mmol) was added anhydrous THF (45 mL). The solution ofN-hydroxysuccinimide ester of (S)-2-hydroxy-3-methylbutyric acid (503mg, 2.34 mmol) in anhydrous THF (4 mL) was added dropwise at RT underN₂. The resulting reaction solution was stirred for 18 h. Less than 5%of starting material remained. All solvent was evaporated under reducedpressure and the residue was dissolved in methanol (200 mL). Thesolution was cooled to 0° C. in an ice-water bath followed by theaddition of aqueous KOH (1 N, 7 mL) to consume excess reagent. Thesolution was stirred at 0° C. for 30 min. Then saturated NH₄Cl (40 mL)was added at 0° C. to neutralize the base. Most of the methanol wasevaporated under reduced pressure and the residue was dissolved in EtOAc(500 mL) followed by washing with saturated NaHCO₃ (100 mL), water(2×100 mL) and brine (100 mL) and dried over Na₂SO₄. The solution wasconcentrated and the crude was purified by flash chromatography elutingwith EtOAc/CH₂Cl₂ gradient (60/40, 70/30, 80/20 and pure EtOAc) toafford the desired product (563 mg, 0.808 mmol, 48% combined yield overthree steps). ¹H NMR (500 MHz, CD₃OD): consistent with proposedstructure. MS: m/z=697.2 (M+1).

Example 17

DMF (1.0 mL) was added to a reaction vial containing the compoundsynthesized in Example 15 (40 mg, 0.067 mmol), (S)-mandelic acid (11 mg,0.072 mmol), and HOBt (11 mg, 0.081 mmol). A few 3 A molecular sievepellets were added and the mixture was stirred for 15 min before theaddition of EDC (15 mg, 0.078 mmol). After 2.5 h, the reaction mixturewas diluted into EtOAc (30 mL) and washed with 1 N aqueous HCl (15 mL),saturated aqueous NaHCO₃ (15 mL) and saturated aqueous NaCl (10 mL). Theorganic layer was dried over Na₂SO₄, decanted, and evaporated. Theresidue was purified by flash column chromatography on silica gel packedin 1:1 EtOAc/CH₂Cl₂, eluting with 3-4% MeOH in 1:1 EtOAc/CH₂Cl₂, to give38 mg of the amide product. MS: m/z=731.1 (M+1).

Examples 18-29

The compounds in Examples 18-29 were prepared using coupling conditionssimilar to those used in Example 17, with the amine synthesized inExample 15 serving as the starting material. Coupling of this amine witha series of carboxylic acids produced the amide derivatives shown inTable 1.

TABLE 1 LCMS m/z Example 18

669.2 (M + 1) Example 19

711.2 (M + 1) Example 20

711.2 (M + 1) Example 21

737.1 (M + 1) Example 22

683.1 (M + 1) Example 23

697.0 (M + 1) Example 24

711.2 (M + 1) Example 25

681.2 (M + 1) Example 26

708.8 (M + 1) Example 27

722.7 (M + 1) Example 28

727.2 (M + 1) Example 29

864.2 (M + 1)

Example 30 Step A

To a dry 15-mL flask were added NaH/mineral oil (60%, 116 mg, 2.91 mmol)and anhydrous hexane (10 mL). The mixture was stirred for 5 min and theupper hexane layer was removed using a syringe. Anhydrous THF (5 mL) wasadded. The mixture was cooled in 0° C. bath for 20 min. Then a solutionof methyl (S)-3-methyl-2-hydroxybutyrate (350 mg, 2.65 mmol) inanhydrous THF (1 mL) was added dropwise at 0° C. over 10 min. After theaddition, the mixture was stirred at 0° C. for 1 h following by theaddition of iodomethane (0.198 mL, 3.18 mmol). The mixture was allowedto warm to RT and was stirred overnight. ¹H NMR showed that there was nostarting material left. The mixture was cooled to 0° C. and aqueous KOH(1 M, 5.4 mL, 5.4 mmol) was added dropwise followed by stirring at RTfor 4 h. The resulting mixture was added to ice (10 g) and wasneutralized by adding aqueous HCl (1 M, 5.5 mL, 5.5 mmol). The mixturewas extracted by ether (3×15 mL), washed with brine (10 mL) and driedover Na₂SO₄. After concentration, the crude product(S)-3-methyl-2-methoxybutanoic acid (251 mg) was used in next step.

Step B

To a dry 15-mL flask with magnetic stir bar were added the aminesynthesized in Example 15 (45 mg, 0.076 mmol), crude(S)-3-methyl-2-methoxybutanoic acid from step A above (12 mg, 0.091mmol), HOBt (12.2 mg, 0.0908 mmol), N,N-diisopropylethylamine (0.0158mL, 0.0908 mmol) and anhydrous DMF (1 mL). The reaction mixture wascooled to 0° C. followed by addition of EDC (17.4 mg, 0.0908). Theresulting reaction mixture was stirred at RT for 18 h. The reaction wasmonitored by LCMS. The reaction mixture was diluted with EtOAc (30mL)/water (10 mL). The organic phase was separated and the aqueous phasewas extracted by EtOAc (2×10 mL). The combined organic layers werewashed with water (20 mL), 10% aqueous NaHSO₄ (20 mL), water (20 mL),saturated NaHCO₃ (20 mL), and brine (2×20 mL), and then dried overNa₂SO₄. After concentration the crude product was purified by PTLCeluting with MeOH/CH₂Cl₂ (7/93) to afford desired product as anoff-white solid (26 mg, 48%). MS: m/z=711.2 (M+1).

Example 31

To a dry flask containing the material synthesized in Example 16 (9.2mg, 0.013 mmol) were added anhydrous THF (0.2 mL) and anhydrous CH₂Cl₂(0.5 mL). All solid dissolved. The solution was cooled in an ice-waterbath for 20 min. Pyridine (0.0085 mL, 0.11 mmol) and acetic anhydride(0.0124 mL, 0.132 mmol) were added at 0° C. The resulting reactionmixture was allowed to warm to RT and was stirred overnight. The mixturewas diluted with EtOAc (20 mL), washed with water (2×10 mL) and brine(10 mL), and dried over Na₂SO₄. After concentration the crude productwas purified by PTLC eluting with MeOH/CH₂Cl₂ (10/90) to afford desiredproduct as an off-white solid (5 mg, 51%). MS: m/z=739.3 (M+1).

Example 32

The compound synthesized in Example 16 (50 mg, 0.072 mmol) was dissolvedin THF (3 mL) and pyridine (57 mg, 0.058 mL, 0.72 mmol) was added at RTunder N₂. The solution was cooled to 0° C. in an ice-water bath followedby the addition of methyl chloroformate (68 mg, 0.055 mL, 0.72 mmol).After stirring at RT overnight, the reaction mixture was dissolved inEtOAc, washed with water and brine, and dried over Na₂SO₄. The solutionwas concentrated and the crude product was purified by flashchromatography to afford the desired product. MS: m/z=755.1 (M+1).

Example 33 Step A

The conditions for this reaction are similar to those used for Example16. The N-hydroxysuccinimide ester of L-Cbz-valine and the materialsynthesized in Example 15 served as the starting materials. MS:m/z=830.1 (M+1).

Step B

To a 15-mL flask containing material synthesized in Step A above (33 mg,0.040 mmol) were added methanol (1 mL) and 10% Pd/C (4.2 mg) under N₂. AH₂ balloon was attached and the flask was purged four times with H₂.Then the H₂ balloon was opened to the reaction system. After 5 hstirring almost no starting material remained. The reaction was stopped.The reaction mixture was filtered through a pad of Celite® and the blackcake was washed with methanol (3×1 mL). The filtrate was concentratedand the crude product was purified by PTLC eluting with MeOH/CH₂Cl₂(15/85) to afford desired product as an off-white solid (13 mg, 47%).MS: m/z=696.2 (M+1).

Example 34 Step A

The conditions for this reaction are similar to those used for Step B ofExample 30. L-Cbz-N-methylvaline and the material synthesized in Example15 served as the starting materials. MS: m/z=844.2 (M+1).

Step B

The conditions for this reaction are similar to those used for Step B ofExample 33. The material synthesized in Step A above served as thestarting material. MS: m/z=710.3 (M+1).

Example 35

The conditions for this reaction are similar to those used for Example31. The material synthesized in Step B of Example 33 served as thestarting material. MS: m/z=738.2 (M+1).

Example 36

The product of Example 36 was prepared by reaction of the amine fromExample 15, using coupling conditions similar to those described forExample 17. Boc-L-proline was used in place of (S)-mandelic acid. Afterisolation of the coupling product, the Boc protecting group was removedby treatment with 4 M HCl in 1,4-dioxane. MS: m/z=694.2 (M+1).

Example 37

The product of Example 37 was prepared by reaction of the amine fromExample 15, using coupling conditions similar to those described forExample 17. trans-Boc-4-hydroxy-L-proline was used in place of(S)-mandelic acid. After isolation of the coupling product, the Bocprotecting group was removed by treatment with 4 M HCl in 1,4-dioxane.EDC/acid, then HCl/dioxane. MS: m/z=710.1 (M+1).

Examples 38-57

The compounds in Examples 38-57 were prepared using coupling conditionssimilar to those used in Example 17, with the amine synthesized inExample 15 serving as the starting material. Coupling of this amine witha series of carboxylic acids produced the amide derivatives shown inTable 2.

TABLE 2 LCMS m/z Example 38

681.2 (M + 1) Example 39

681.2 (M + 1) Example 40

695.1 (M + 1) Example 41

708.8 (M + 1) Example 42

679.0 (M + 1) Example 43

678.7 (M + 1) Example 44

692.8 (M + 1) Example 45

747.2 (M + 1) Example 46

759.0 (M + 1) Example 47

758.7 (M + 1) Example 48

665.1 (M + 1) Example 49

679.0 (M + 1) Example 50

692.8 (M + 1) Example 51

706.8 (M + 1) Example 52

720.8 (M + 1) Example 53

695.1 (M + 1) Example 54

695.1 (M + 1) Example 55

779.0 (M + 1) Example 56

694.8 (M + 1) Example 57

813.2 (M + 1) Example 58

813.2 (M + 1)

Example 59

The compound synthesized in Example 15 (25 mg, 0.042 mmol) was dissolvedin THF (1.0 mL) in a small reaction vial. A few 3 A molecular sievepellets were added along with 4-methylmorpholine (0.007 mL, 6 mg, 0.06mmol), followed by 3,4,5-trimethoxybenzoyl chloride (10 mg, 0.043 mmol).After 3 h, the reaction mixture was diluted into EtOAc (30 mL) andwashed with 1 N aqueous HCl (15 mL), saturated aqueous NaHCO₃ (15 mL)and saturated aqueous NaCl (10 mL). The organic layer was dried overNa₂SO₄, decanted, and evaporated. The residue was purified by flashcolumn chromatography on silica gel packed in 1:1 EtOAc/CH₂Cl₂, elutingwith 3% MeOH in 1:1 EtOAc/CH₂Cl₂, to give 25 mg of the amide product asa white solid. MS: m/z=791.1 (M+1).

Examples 60-65

The compounds in Examples 60-65 shown in Table 3 were prepared usingcoupling conditions similar to those used in Example 59, with the aminesynthesized in Example 15 serving as the starting material. Coupling ofthis amine with a series of carboxylic acid chlorides produced the amidederivatives. N,N-Diisopropylethylamine was substituted for4-methylmorpholine as the base.

TABLE 3 LCMS m/z Example 60

680.8 (M + 1) Example 61

694.8 (M + 1) Example 62

694.8 (M + 1) Example 63

706.7 (M + 1) Example 64

720.8 (M + 1) Example 65

796.7 (M + 1)

Example 66

The conditions for this reaction are similar to those used for Step B ofExample 30. Formic acid and the material synthesized in Example 15served as the starting materials. MS: m/z=624.8 (M+1).

Example 67

The compound synthesized in Example 15 (17 mg, 0.028 mmol) was dissolvedin THF (3 mL). Geranyl bromide (0.006 mL, 0.028 mmol) andN,N-diisopropylethylamine (0.01 mL, 0.056 mmol) were added at 0° C.under N₂. After stirring overnight at RT, the solvent was removed atreduced pressure and the residue was purified by flash chromatography toafford the desired product. MS: m/z=733.2 (M+1).

Example 68

The compound synthesized in Example 15 (20 mg, 0.034 mmol) was dissolvedin THF (1.0 mL) in a small reaction vial. A few 3 A molecular sievepellets were added along with 4-methylmorpholine (0.007 mL, 6 mg, 0.06mmol), followed by 1 M isopropyl chloroformate in toluene (0.037 mL,0.037 mmol). After 4 h, the reaction mixture was diluted into EtOAc (30mL) and washed with 1 N aqueous HCl (15 mL), saturated aqueous NaHCO₃(15 mL) and saturated aqueous NaCl (10 mL). The organic layer was driedover Na₂SO₄, decanted, and evaporated. The residue was purified by flashcolumn chromatography on silica gel packed in 1:1 EtOAc/CH₂Cl₂, elutingwith 2% MeOH in 1:1 EtOAc/CH₂Cl₂, to give 19 mg of the carbamateproduct. MS: m/z=683.1 (M+1).

Examples 69-72

The compounds in Examples 69-72 shown in Table 4 were prepared usingcoupling conditions similar to those used in Example 68, with the aminesynthesized in Example 15 serving as the starting material. Coupling ofthis amine with a series of alkyl chloroformates produced the carbamatederivatives. N,N-Diisopropylethylamine was substituted for4-methylmorpholine as the base. For Example 72,S-propylchlorothioformate was used in the reaction.

TABLE 4 LCMS m/z Example 69

696.7 (M + 1) Example 70

678.7 (M + 1) Example 71

680.7 (M + 1) Example 72

698.7 (M + 1)

Example 73

The compound synthesized in Example 15 (25 mg, 0.042 mmol) was dissolvedin THF (1.0 mL) in a small reaction vial. A few 3 A molecular sievepellets were added along with 4-methylmorpholine (0.007 mL, 6 mg, 0.06mmol), followed by methanesulfonyl chloride (0.0035 mL, 5.2 mg, 0.045mmol). After 3 h, the reaction mixture was diluted into EtOAc (30 mL)and washed with 1 N aqueous HCl (15 mL), saturated aqueous NaHCO₃ (15mL) and saturated aqueous NaCl (10 mL). The organic layer was dried overNa₂SO₄, decanted, and evaporated. The residue was purified by flashcolumn chromatography on silica gel packed in 1:1 EtOAc/CH₂Cl₂, elutingwith 3% MeOH in 1:1 EtOAc/CH₂Cl₂, to give 18 mg of the sulfonamideproduct as a white solid. MS: m/z=675.0 (M+1).

Examples 74-75

The compounds in Examples 58-63 shown in Table 5 were prepared usingcoupling conditions similar to those used in Example 73, with the aminesynthesized in Example 15 serving as the starting material. Coupling ofthis amine with a series of sulfonyl chlorides produced the sulfonamidederivatives. In the case of Example 75, N,N-diisopropylethylamine wassubstituted for 4-methylmorpholine as the base.

TABLE 5 LCMS m/z Example 74

737.0 (M + 1) Example 75

742.7 (M + 1)

Example 76 Step A

The conditions for this reaction are similar to those used for Example10. L-Tryptophan methyl ester hydrochloride and the material synthesizedin Example 9 served as the starting materials. MS: m/z=873.2 (M+1).

Step B

A solution of DDQ (411 mg, 1.81 mmol) in THF (5 mL) was added to thecompound synthesized in Step A above (720 mg, 0.824 mmol) in THF (15 mL)and the dark solution was heated to gentle reflux in an oil bath at 85°C. for 1.5 h. After cooling, the solvent was removed on a rotaryevaporator. The residue was diluted with EtOAc (200 mL), washed withsaturated NaHCO₃ (50 mL), water (2×50 mL) and brine (50 mL), and driedover Na₂SO₄. After concentration the crude product was purified bysilica gel chromatography eluting with EtOAc/hexanes (40/60 to 45/55) toafford desired product as a brownish yellow solid (427 mg, 60%). MS:m/z=869.1 (M+1).

Step C

To a dry flask containing the material synthesized in Step B above (44mg, 0.051 mmol) was added anhydrous acetonitrile (12 mL). The solutionwas transferred to two quartz tubes and argon was bubbled through thesolutions for 30 min. The solutions were cooled to −30° C. and asolution of sodium bis(trimethylsilyl)amide in THF (1.0 M, 0.061 mL,0.061 mmol) was added dropwise over 5 min. The resulting cold solutionwas irradiated by UV for 30 min and quenched by addition of aqueoussaturated NH₄Cl (2 mL). The mixture was extracted by EtOAc (2×50 mL) andthe combined organic layers were washed with saturated aqueous NH₄Cl (10mL), water (2×10 mL) and brine (10 mL), and dried over Na₂SO₄. Afterconcentration the crude product was purified by PTLC eluting withMeOH/CH₂Cl₂ (8/92) to afford desired product as an off-white solid (3.5mg, 9%). MS: m/z=789.0 (M+1).

Step D

To a 15-mL flask containing the material synthesized in Step C above(3.5 mg, 0.00443 mmol) was added methanol (1 mL) and 20% Pd(OH)₂/C (5.0mg) under N₂. A H₂ balloon was attached and the flask was purged fourtimes with H₂. Then the H₂ balloon was opened to the reaction system.After 4 h stirring almost no starting material remained. The reactionwas stopped. The reaction mixture was filtered through a pad of Celite®and the black cake was washed with methanol (3×1 mL). The filtrate wasconcentrated and the crude product was used in next step.

Step E

The conditions for this reaction are similar to those used for Example16. The N-hydroxysuccinimide ester of (S)-2-hydroxy-3-methylbutyric acidand the material synthesized in Step D above served as the startingmaterials. MS: m/z=755.2 (M+1).

Example 77

The conditions for this reaction are similar to those used for Step B ofExample 80. The material synthesized in Step A Example 80 and(S)-2-hydroxy-3-methylbutyric acid served as the starting materials. MS:m/z=713.3 (M+1).

Example 78 Step A

To a dry flask containing the material synthesized in Example 13 (55 mg,0.074 mmol) was added Cs₂CO₃ (36 mg, 0.11 mmol), anhydrous DMF (1 mL)and iodomethane (0.023 mL, 0.37 mmol). The resulting reaction mixturewas stirred at RT overnight. The mixture was diluted with EtOAc (30 mL),washed with water (3×10 mL) and brine (2×10 mL), and dried over Na₂SO₄.After concentration the crude product was purified by PTLC eluting withMeOH/CH₂Cl₂ (5/95) to afford desired product as an off-white solid (20mg, 36%). MS: m/z=761.2 (M+1).

Step B

The conditions for this reaction are similar to those used for Step D ofExample 76. The material synthesized in Step A above served as thestarting material. The crude product was used in next step.

Step C

The conditions for this reaction are similar to those used for Example16. The N-hydroxysuccinimide ester of (S)-2-hydroxy-3-methylbutyric acidand the material synthesized in Step B above served as the startingmaterials. MS: m/z=727.2 (M+1).

Example 79

The product of Example 79 was isolated as a second product from thereaction described in Example 78. MS: m/z=741.3 (M+1).

Example 80 Step A

To a 50-mL flask containing the product from Example 13 (153 mg, 0.21mmol) and 10% Pd/C (30 mg) was added methanol (5 mL) and triethylamine(0.086 mL, 0.62 mmol) under N₂. The flask was purged with H₂ using a H₂balloon and the mixture was stirred under H₂ at RT. After 3 h thereaction mixture was filtered through a 0.45 micron filter. The filtratewas concentrated and the residue was used directly in next step withoutfurther purification. The structure of the product was confirmed byLCMS.

Step B

To a solution of the product from Step A above (84 mg, 0.14 mmol),2-ethyl-2-hydroxybutyric acid (21.8 mg, 0.165 mmol) and HOBt (22.2 mg,0.165 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.036 mL,0.206 mmol), followed by EDC (31.5 mg, 0.165 mmol) at RT. After stirringfor 12 h, the reaction solution was diluted with EtOAc (100 mL), andwashed with 1 N HCl (20 mL), water (20 mL), saturated NaHCO₃ (20 mL) andbrine (20 mL). After drying over Na₂SO₄, the solution was concentratedand the crude was purified by flash chromatography eluting withMeOH/CH₂Cl₂ gradient (5/95) to afford the desired product. MS: m/z=727.0(M+1).

Example 81

The conditions for this reaction are similar to those used for Step B ofExample 80. The material synthesized in Step B of Example 78 and2-ethyl-2-hydroxybutyric acid served as the starting materials. MS:m/z=741.2 (M+1).

Example 82

The product of Example 82 was isolated as a second product from thereaction described in Example 81. MS: m/z=755.1 (M+1).

Example 83

To a dry flask containing the material synthesized in Example 16 (7.0mg, 0.01 mmol) was added the solution of NCS (7.3 mg, 0.055 mmol) inanhydrous THF (0.8 ml). The reaction solution was stirred at RT for 18 hunder N₂. The reaction was monitored by LCMS. The reaction mixture wasdiluted with EtOAc (50 ml), followed by washing with water (2×20 ml) andbrine (10 ml). The solution was dried over Na₂SO₄ and concentrated. Thecrude product was purified by PTLC eluting with MeOH/CH₂Cl₂ (8/92) toafford desired product as an off-white solid (7 mg, 88%). MS: m/z=799.0(M+1).

Example 84

To a dry flask were added the material synthesized in Example 16 (33 mg,0.047 mmol) and anhydrous THF (1 mL). All of the solid dissolved. Astock solution of NBS (12.6 mg, 0.071 mmol) in anhydrous THF (1 mL) wasadded dropwise at RT. After the addition, the reaction solution wasstirred at RT for 18 h. The reaction was monitored by LCMS. All of thestarting material was consumed. The reaction mixture was diluted withEtOAc (30 mL), washed with water (2×10 mL) and brine (10 mL), and driedover Na₂SO₄. The crude product was purified by PTLC (elute: EtOAc) toafford the desired product (8.1 mg, 22%). The structure was confirmed byLCMS [m/z=774.6 (M+1)] and ¹H NMR (CD₃OD, 400 MHz).

Example 85 Step A

To a dry flask containing the product from Example 84 (5 mg, 0.00645mmol) was added anhydrous THF (0.5 mL). A stock solution of NCS (2.2 mg,0.016 mmol) in THF (1 mL) was added dropwise at RT. The reactionsolution was stirred at RT for 3 h. The reaction was monitored by LCMS.No starting material remained. The reaction mixture was diluted withEtOAc (30 mL), washed with water (2×10 mL) and brine (10 mL), and driedover Na₂SO₄. The crude was purified by PTLC (elute: EtOAc) to afford thedesired product (2.3 mg, 42%). MS: m/z=842.5 (M+1).

Step B

Diazonamide A (Reference Example)

To a flask containing the product from Step A above (2.3 mg, 0.0027mmol) was added methanol (1.5 mL). Under N₂ atmosphere 10% Pd/C (1.4 mg)was added. A H₂ balloon was attached immediately and the flask waspurged with H₂ four times. The reaction proceeded for 2 h. The mixturewas filtered through a pad of Celite® and the residue was washed withMeOH (2×2 mL). The filtrate was concentrated and purified by PTLC(elute: EtOAc) to afford the desired product (2.0 mg, 96%). Thestructure was confirmed by LCMS [m/z=764.7 (M+1)] and ¹H NMR (CD₃OD, 400MHz).

Example 86 Step A

To a dry flask containing the material synthesized in Example 84 (5 mg,0.0065 mmol) was added anhydrous THF (0.5 mL). A stock solution of NCS(2.2 mg, 0.0161 mmol) in THF (1 mL) was added dropwise at RT. Thereaction solution was stirred at RT for 3 h. The reaction was monitoredby LCMS. No starting material remained. The reaction mixture was dilutedwith EtOAc (30 mL), washed with water (2×10 mL) and brine (10 mL), anddried over Na₂SO₄. The crude product was purified by PTLC (elute: EtOAc)to afford the desired product (1.5 mg, 29%). MS: m/z=808.5 (M+1).

Step B

The conditions for this reaction are similar to those used in Step B ofexample 85. MS: m/z=730.7 (M+1).

Example 87

The product of Example 87 was prepared using reaction conditions similarto those described in Example 84. The material synthesized in Example 24served as the starting material. MS: m/z=788.5 (M+1).

Example 88

The product of Example 88 was prepared using conditions similar to thosedescribed in Example 89. The material synthesized in Example 24 servedas the starting material. MS: m/z=868.5 (M+1).

Example 89 Step A

To a dry flask were added the material synthesized in Example 16 (33 mg,0.047 mmol) and anhydrous THF (1 mL). All of the solid dissolved. Astock solution of NBS (12.6 mg, 0.071 mmol) in anhydrous THF (1 mL) wasadded dropwise at RT. The reaction solution was stirred at RT for anadditional 18 hrs. The reaction was monitored by LCMS. All startingmaterial was consumed. The reaction mixture was diluted with EtOAc (30mL), washed with water (2×10 mL) and brine (10 mL), and dried overNa₂SO₄. The crude product was purified by PTLC (elute: EtOAc) to affordthe desired product (11.5 mg, 28%). MS: m/z=852.5 (M+1).

Step B

To a dry flask containing the material synthesized in example 70 (5.5mg, 0.0064 mmol) was added anhydrous THF (0.5 mL). A stock solution ofNCS (3.4 mg, 0.026 mmol) in THF (1 mL) was added dropwise at RT. Thereaction solution was stirred at RT for 3 h. The reaction was monitoredby LCMS. No starting material remained. The reaction mixture was dilutedwith EtOAc (30 mL), washed with water (2×10 mL) and brine (10 mL), anddried over Na₂SO₄. The crude product was purified by PTLC eluting withMeOH/CH₂Cl₂ (7/93) to afford the desired product (3.5 mg, 62%). MS:m/z=886.5 (M+1).

Step C

The conditions for this reaction are similar to those used in Step B ofexample 85. MS: m/z=808.5 (M+1).

Example 90

The product of Example 90 was prepared using reaction conditions similarto those described for Example 85. The material synthesized in Example87 served as the starting material. MS: m/z=778.7 (M+1).

Example 91

The product of Example 91 was isolated as a minor product from thereaction described in Example 90. MS: m/z=812.5 (M+1).

Example 92

Chemical Formula: C₃₈H₃₀F₃N₇O₆

Exact Mass: 737.22; Molecular Weight: 737.68

Isolated as a 2:1 mixture of diastereomers.

Example 93 Additional Compounds

The compounds shown in Table 6 are also available by the methods of theinvention as described herein.

TABLE 6

Example 93a

Example 93b

Example 93c

Example 93d

Example 93e

Example 93f

Example 93g

Example 93h

Example 93i

Example 94 Cell Viability Assay Protocol

Cell viability assays were run using standard protocols known to thoseof skill in art. Cells were plated in 96 well plates at the density of3,000-10,000 cells per well. Twenty four hours later, cells were treatedwith increasing concentration of test compounds (1 nM to 1 μM). Afteranother 48 hour, cell survival was measured using CELL-TITER-GLO®reagent (Promega) following the protocol provided by the manufacture.The IC₅₀ value was determined as the concentration of test compound thatkills 50% of the cell population.

Example 95 Representative Biological Data

Cell viability data generated according to the protocol described hereinwas generated for representative compounds in the A2058 (human melanoma)and U937 (human leukemic monocyte lymphoma) cell lines. Data areprovided below in Table 7. The compound of Example 16 (“Compound J”) wasused as a reference compound.

TABLE 7 Representative Cell Viability Data IC₅₀ (μM) Example # A2058U937 16 0.043 0.034 (Cpd J) 17 0.630 0.465 18 0.394 0.208 19 0.222 0.06220 0.158 0.142 21 >1 >1 22 0.230 0.146 23 0.124 0.156 24 0.105 0.062 250.769 0.420 26 0.214 0.154 27 0.181 0.128 28 0.208 0.133 29 >1 >1 300.197 0.224 31 0.194 0.062 32 0.211 0.157 33 1.444 0.572 34 0.221 0.39335 0.232 0.183 36 >1 >1 37 >1 >1 38 0.417 0.216 39 0.707 0.555 40 0.2330.164 41 0.397 0.220 42 0.409 0.221 43 0.356 0.186 44 0.587 0.399 450.887 0.780 46 0.313 0.443 47 0.546 0.323 48 0.457 0.220 49 0.443 0.24550 0.339 0.331 51 0.235 0.276 52 0.386 0.491 53 0.209 0.078 54 0.0810.078 55 0.613 0.406 56 >1 0.756 57 0.580 0.618 58 >1 0.821 59 0.7980.619 60 0.538 0.255 61 0.636 0.550 62 0.556 0.247 63 0.488 0.20664 >1 >1 65 0.796 0.509 66 0.766 0.499 67 >1 >1 68 0.451 0.214 69 0.5410.272 70 0.692 0.434 71 0.451 0.185 72 0.600 0.543 73 0.140 0.067 740.429 >1 75 >1 >1 76 0.013 0.018 77 0.070 0.052 78 0.042 0.051 79 0.0220.027 80 0.183 0.182 81 0.123 0.054 82 0.029 0.021 83 0.630 0.693 840.510 0.648 85 0.057 0.086 86 0.081 0.084 87 >1 >1 88 >1 >1 89 0.1580.079 90 0.375 0.302 91 >1 >1 92 >1 0.750

Example 96 Cell Profiling Data

(Example 24)

The compound prepared in Example 24 has been shown to kill tumor cellsin cell lines derived from a variety of origins. Data is provided inTable 8.

TABLE 8 Cell profiling data for the compound of Example 24 Tumor Cellline Origin IC₅₀ (μM) U937 Blood 0.044 MDA-MB231 Breast 0.234 MDA-MB435Breast 0.029 Colo205 Colon 0.144 DLD-1 Colon 0.515 HT29 Colon 0.090 LovoColon 0.150 T98G Glial Cells 0.067 HCC1437 Lung 0.195 HCC44 Lung 0.036NCI-H226 Lung 0.104 NCI-H460 Lung 0.242 SKMES-1 Lung 0.470 BxPC3Pancreas 0.213 MiaPaca-2 Pancreas 0.111 Panc-1 Pancreas 0.288 PL45Pancreas 0.113 SW1990 Pancreas 0.360 DU145 Prostate 0.057 A2058 Skin0.093 A375 Skin 0.162 G361 Skin 0.275 SKMEL-5 Skin 0.070

Example 97 Xenograft Models—General Protocol

Experimental Design

Animals: Athymic nude mice, female, 6-7 weeks old, 20-25 g. Animalsbearing with 180-400 mg tumors were selected for experiment. 7mice/group.

Administration: Tail vein injection, 200 μL/mouse, to provide the doseindicated.

Dosing schedule: 6 injections were given on the days indicatedpost-tumor cell injection.

Controls: Vehicle, Compound J at 20 mg/kg.

Test Compound preparation: Compound J and all test compounds weredissolved in 50% Cremophore/EtOH (1:1) at 10 mg/mL as stock solution.Each compound solution was diluted with saline before injection to theconcentration indicated.

Example 98 MiaPaca Xenograft Models

Experimental Design

Xenograft Model: MiaPaca (pancreatic cancer) cells

Dosing schedule: 6 injections were given on days 9, 11, 14, 16, 18 and21 post-tumor cell injection.

Test Compounds: Example 23, Example 24, and Example 53, at 20 mg/kg.

Controls: Vehicle, Compound J at 20 mg/kg.

Results

The inhibition of tumor growth in the MiaPaca xenograft model is shownin FIG. 1, which shows tumor volume (mL³) versus days post tumor cellinjection. Treatment with the test compounds did not significantlyaffect body weight (data not shown). The number of tumor free animals at35 days post tumor-cell injection for representative compounds is shownin Table 9. For animals treated with the compound of Example 24 at 20mg/kg, 7 of 7 animals were tumor free at 35 days post tumor cellinjection.

TABLE 9 Test Compound (dose) Tumor free animals (days) Control 0/7 (35)Ex. 16 (20 mg/kg) 0/7 (35) Ex. 53 (20 mg/kg) 1/7 (35) Ex. 23 (20 mg/kg)0/7 (35) Ex. 24 (20 mg/kg) 7/7 (35)

Example 99 MDA-MB-231-N1 Xenograft Model

Experimental Design

Xenograft Model: MDA-MB-231-N1 (breast cancer) cells.

Dosing schedule: 6 injections were given on days 6, 8, 11, 13, 15 and 18post-tumor cell injection.

Test Compounds: Example 24 and Diazonamide A at 20 mg/kg.

Controls: Vehicle, Compound J at 20 mg/kg.

Results

The inhibition of tumor growth in the MDA-MB-231-N1 xenograft model isshown in FIG. 2.

Example 100 Colo205 Xenograft Model

Experimental Design

Xenograft Model: Colo205 (colon cancer) cells.

Dosing schedule: 6 injections were given on days 7, 9, 12, 14, 16 and 19post-tumor cell injection.

Test Compounds: Example 24 at 20 mg/kg.

Controls: Vehicle.

Results

The inhibition of tumor growth in the Colo205 xenograft model is shownin FIG. 3.

Example 101 MDA-MB231N1 Xenograft Model

Experimental Design

Xenograft Model: MDA-MB231N1 (breast cancer) cells

Dosing schedule: 6 injections were given on days 6, 8, 11, 13, 15 and 18post-tumor cell injection.

Test Compounds: Example 24 at 40 mg/kg, 20 mg/kg and 10 mg/kg.

Control: Vehicle.

Results

The comparative inhibition of tumor growth in the MDA-MB231N1 xenograftmodel at three doses is shown in FIG. 4.

Example 102 MDA-MB435 Xenograft Model

Experimental Design

Xenograft Model: MDA-MB435 (breast cancer) cells.

Dosing schedule: 6 injections were given on days 21, 23, 25, 28, 30 and32 post-tumor cell injection.

Test Compounds: Example 24 at 20 mg/kg.

Control: Vehicle.

Results

The inhibition of tumor growth in the MDA-MB435 xenograft model is shownin FIG. 5.

Example 103 MiaPaca Xenograft Model

Experimental Design

Xenograft Model: MiaPaca (pancreatic cancer) cells.

Dosing schedule: 6 injections were given on days 7, 9, 11, 14, 16 and 18post-tumor cell injection.

Test Compounds: Example 24 at 20 mg/kg and 10 mg/kg.

Control: Vehicle.

Results

The inhibition of tumor growth in the MiaPaca xenograft model at twodoses is shown in FIG. 6.

Example 104 HT29 Xenograft Model

Experimental Design

Xenograft Model: HT29 (colon cancer) cells.

Dosing schedule: 6 injections were given on days 7, 9, 12, 14, 16 and 19post-tumor cell injection.

Test Compounds: Example 24 at 40 mg/kg.

Control: Vehicle.

Results

The inhibition of tumor growth in the HT29 xenograft model is shown inFIG. 7.

Example 105 HPAC Xenograft Model

Experimental Design

Xenograft Model: HPAC (pancreatic cancer) cells.

Dosing schedule: 6 injections were given on days 7, 9, 11, 14, 16 and 18post-tumor cell injection.

Test Compounds: Example 24 at 20 mg/kg.

Control: Vehicle.

Results

The inhibition of tumor growth in the HPAC xenograft model is shown inFIG. 8.

Example 106 A2058 Xenograft Model

Experimental Design

Xenograft Model: A2058 (melanoma) cells.

Dosing schedule: 6 injections were given on days 2, 4, 7, 9, 11 and 14post-tumor cell injection.

Test Compounds: Example 24 at 40 mg/kg and 20 mg/kg.

Control: Vehicle.

Results

The inhibition of tumor growth in the A2058 xenograft model is shown inFIG. 9.

The entirety of each patent, patent application, publication anddocument referenced herein hereby is incorporated by reference. Citationof the above patents, patent applications, publications and documents isnot an admission that any of the foregoing is pertinent prior art, nordoes it constitute any admission as to the contents or date of thesepublications or documents.

Modifications may be made to the foregoing without departing from thebasic aspects of the invention. Although the invention has beendescribed in substantial detail with reference to one or more specificembodiments, those of ordinary skill in the art will recognize thatchanges may be made to the embodiments specifically disclosed in thisapplication, and yet these modifications and improvements are within thescope and spirit of the invention.

The invention claimed is:
 1. A compound having the formula (V):

or a pharmaceutically acceptable salt or conjugate thereof; wherein R¹is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C6 aryl, C6-C12arylalkyl, or a heteroform of one of these, each of which may beoptionally substituted; R² is H, or C1-C8 alkyl, C1-C8 heteroalkyl,C6-C14 arylalkyl, C6-C14 heteroarylalkyl, each of which may beoptionally substituted; or R¹ and R² may be taken together with theatoms to which they are attached to form an optionally substituted 5- to7-membered azacyclic ring, optionally containing an additionalheteroatom selected from N, O, and S as a ring member; R⁸ and R⁹ areindependently H, halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,C6-C12 aryl, C5-C12 heteroaryl, each of which may be optionallysubstituted, or COOR¹¹ or CONR¹¹ ₂, where each R¹¹ is independently H orC1-C4 alkyl; m and m″ are independently 0-3; and each Y and Y″ isindependently halo, OH, C1-C4 alkoxy, or C1-C8 alkyl, C2-C8 alkenyl,C2-C8 alkynyl, C6-C12 aryl, or C6-C14 arylalkyl, or a heteroform of oneof these, each of which may be optionally substituted; Z is OH, OR,CH₂OR, SR, or NR₂, where each R is independently H, optionallyfluorinated C1-C4 alkyl, or optionally fluorinated C1-C4 acyl; and eachof R^(10a) and R^(10b) is independently C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, C6-C12 aryl,C6-C20 arylalkyl, or a heteroform of one of these, each of which may beoptionally substituted; or R^(10a) and R^(10b) may be taken togetherwith the carbon to which they are attached to form a C3-C8 cycloalkyl ora C3-C8 heterocyclyl ring, which may be optionally substituted, providedthe compound is not:

wherein: (a) R¹ and R² are taken together with the atoms to which theyare attached to form an optionally substituted 5- to 7-memberedazacyclic ring, optionally containing an additional heteroatom selectedfrom N, O, and S as a ring member; (b) at least one of R⁸ and R⁹ isCOOR¹¹ or CONR¹¹ ₂; (c) Z is OH; (d) R^(10a) and R^(10b) are the same;(e) R^(10a) and R^(10b) are taken together with the carbon to which theyare attached to form a C3-C8 cycloalkyl or a C3-C8 heterocyclyl ring,which may be optionally substituted, and which may be optionally fusedto a substituted or unsubstituted phenyl ring to provide an indenyl ortetrahydronaphthyl ring system; or (f) each of m and m″ is 0 or 1; Y ishalo when m is 1; and Y″ is halo, OH, or C1-C4 alkoxy when m″ is
 1. 2. Acompound of claim 1, having the formula:

or a pharmaceutically acceptable salt or conjugate thereof.
 3. Acompound of claim 1, having the formula:

or a pharmaceutically acceptable salt or conjugate thereof.
 4. Acompound of claim 1 wherein R¹ is optionally substituted C1-C4 alkyl,C2-C4 alkenyl or C2-C4 alkynyl.
 5. A compound of claim 1 wherein R¹ isisopropyl.
 6. A compound of claim 1 wherein R² is H or C1-C4 alkyl.
 7. Acompound of claim 1 wherein R² is H or methyl.
 8. A compound of claim 1wherein R¹ and R² are taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered azacyclicring, optionally containing an additional heteroatom selected from N, O,and S as a ring member.
 9. A compound of claim 1 wherein R⁸ and R⁹ areindependently H, halo, or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,C6-C12 aryl, or C5-C12 heteroaryl, each of which may be optionallysubstituted.
 10. A compound of claim 1 wherein at least one of R⁸ and R⁹is halo.
 11. A compound of claim 1, wherein each of R⁸ and R⁹ isindependently H or Cl.
 12. A compound of claim 1 wherein R⁸ and R⁹ areboth chloro or both H.
 13. A compound of claim 1 wherein at least one ofR⁸ and R⁹ is COOR¹¹ or CONR¹¹ ₂.
 14. A compound of claim 1 wherein eachof m and m″ is 0 or
 1. 15. A compound of claim 1 wherein each of m andm″ is 0 or 1 and each of Y and Y″ is halo, OH or OMe.
 16. A compound ofclaim 1 wherein each of m and m″ is
 0. 17. A compound of claim 1 whereinZ is OH, OMe, OAc, CH₂OH, SH, SMe, SAc, NH₂, NHMe, NMe₂, or NHAc.
 18. Acompound of claim 1 wherein Z is OH.
 19. A compound of claim 1 whereinR^(10a) and R^(10b) are the same.
 20. A compound of claim 1, whereineach of R^(10a) and R^(10b) is an optionally substituted C1-C6 alkyl.21. A compound of claim 1 wherein R^(10a) and R^(10b) are taken togetherwith the carbon to which they are attached to form a C3-C8 cycloalkyl ora C3-C8 heterocyclyl ring, which may be optionally substituted, andwhich may be optionally fused to a substituted or unsubstituted phenylring to provide an indenyl or tetrahydronaphthyl ring system.
 22. Thecompound of claim 1, wherein each of m and m″ is 0 or 1; Y is halo whenm is 1; and Y″ is halo, OH, or C1-C4 alkoxy when m″ is
 1. 23. A methodof ameliorating a cell proliferative disorder comprising administeringto a human subject in need thereof a therapeutically effective amount ofa compound of claim 1, thereby ameliorating the cell proliferationdisorder, wherein the cell proliferation is selected from breast cancer,prostate cancer, or lung adenocarcinoma.